Song appeared in two episodes of the television program Thunder Alley, and was a regular in the children's television series Fudge, in which she portrayed Jenny. Her theatrical film debut was in Santa with Muscles, a 1996 independent film starring professional wrestler Hulk Hogan. After a small role in Leave It to Beaver (1997), she appeared in the Nickelodeon television series 100 Deeds for Eddie McDowd, where she played Sariffa Chung in thirteen episodes. After 100 Deeds, she had a number of small parts in television shows such as 7th Heaven, Judging Amy, ER, Once and Again, and Bette, where she met Ashley Tisdale.
Two of Song's early roles led to recognition in the Young Artist Awards. Her role in the 2000 Disney Channel Original Movie The Ultimate Christmas Present won her the award for "Best Performance in a TV Movie Comedy, Supporting Young Actress". The film centers on two teenage girls, Allison Thompson (Hallee Hirsh) and Samantha Kwan (Song), who find a weather machine and make it snow in Los Angeles. Her 2002 appearance on The Bernie Mac Show led to a nomination for "Best Performance in a TV Comedy Series, Guest Starring Young Actress". In the same year, she was in the 20th Century Fox family film Like Mike, which grossed over $60 million. The film stars rapper Bow Wow as an orphan who can suddenly play NBA-level basketball. Song portrays the character Reg Stevens, a thirteen-year old orphan. Although the film was criticized for its "frightening myths about adoption", it was successful enough to spawn a sequel. Song did not participate in the sequel.
In 2002, Song signed a contract with Disney and appeared in the Disney Channel movie Get a Clue. After 2002, Song continued to make guest appearances in American situation comedies such as That's So Raven and One on One. She had a recurring role as Tia in the Disney Channel series Phil of the Future, appearing in seven episodes of the series in 2004 and 2005.
In late 2004, Song starred in the Disney Channel Original Movie Stuck in the Suburbs, portraying Natasha Kwon-Schwartz. The television premiere received 3.7 million viewers. The film is about two teenage girls living in suburbia who accidentally exchange cell phones with a famous teen musician. She later said: "When Stuck came out it was crazy 'cause we went to Six Flags and we were there and so many kids recognized us from Stuck in the Suburbs, I'm like wow that movie must have done really well." That year, Song posed for the cover of Teen People with her Get a Clue co-star, Lindsay Lohan.
In 2005, Song began appearing in the role of spoiled heiress London Tipton in the Disney Channel Original Series, The Suite Life of Zack & Cody. The role was named "Paris" in an early script and alludes to Paris Hilton (London spoofing Paris, and Tipton is the name of the hotel her father owns in the show). She got the role without an audition and was surprised to find her friend, Ashley Tisdale, working in the show. Song says, "London is my fantasy person, I wish I could be her. I wish I had her closet."
After her debut on the Suite Life series, Song became a regular on the Disney Channel, and had a voice role in Disney Channel's American Dragon: Jake Long series. In 2006, Song had a voice-over role in Holidaze: The Christmas That Almost Didn't Happen. She later starred in an online series called London Tipton's Yay Me! based on the episode "Tiptonline" on The Suite Life of Zack and Cody.
Song's first starring role as the title character was in the 2006 Disney Channel Original Movie Wendy Wu: Homecoming Warrior, which had over 5.7 million viewers at its premiere. Wendy Wu was planned to be a comedy, but the directors of the film were having trouble finding a suitable actor with both the comedic presence and taekwondo ability to play the main character, originally named Kenny Lu. Lydia Cook, one of the films's directors, said, "Brenda was originally brought in to play the [supporting] monk’s role. We started training with her in martial arts, and that’s when we realized that she should be Kenny Lu. They quickly switched things around and offered Brenda the lead in the movie. She had the perfect combination of wit and martial arts." Song had to break a brick with her hand in a screen test before landing the title role.
In 2008 Song appeared in the Walt Disney Pictures film College Road Trip with Raven-Symoné and Martin Lawrence. In its opening weekend in March 2008, the film grossed $13.6 million, ranking #2 at the box office. The family film centers on college-bound teen Melanie Porter (Symoné), who goes on a road trip to different colleges with her father, while her college-bound friends Nancy Carter (Song) and Katie (Margo Harshman) surprise Melanie on her road trip. The film grossed $45 million in the United States and $6 million outside the United States. Although it earned a Teen Choice Award nomination for "choice movie comedy", the film mainly received negative reviews, and critics panned the acting. A Daily Mail review said the film was "one of those churn-'em-out Disney comedies in which every performer seems to be competing to give the most annoying performance in cinematic history."
After being a captain for three years in the Disney Channel Games, Song was featured in Studio DC: Almost Live with other Disney stars. She had guest voice roles in Phineas & Ferb and The Emperor's New School. She starred in the Lifetime Movie Network telefilm Special Delivery, a film about bonded courier, Maxine (Lisa Edelstein), who is forced to take care of a 14-year old troubled teen, Alice (Song). The Daily Record called it a "likeable comedy". The Australian publication Urban CineFilm gave Song a positive review for her performance in the film.
Song reprised her role as London Tipton in the 2008 Suite Life spin-off/sequel, The Suite Life on Deck. The show's premiere on the Disney Channel drew 5.7 million viewers, and it became the most-watched series premiere on Canada's Family Channel. The show became the most-watched scripted series among children aged 6 to 11 and among tweens in 2008. In 2009, the show was the most-watched scripted series among children and the second most-watched scripted series among pre-teens. Disney ordered a second season for the series, which aired in August 2009. In May 2009, Disney Channel's executive vice president Gary Marsh issued a press release, which stated: "with this second-season extension, the cast of 'The Suite Life' makes Disney Channel history by becoming the longest running continuous characters on our air – 138 half-hour episodes. We are thrilled for them, and for the brilliant, inspired production team that made this extraordinary run possible." Song's character, London Tipton, is Disney Channel's longest continuous female character.
Song starred as Paige in a December 2013 animated TV special for NBC, "Macy's Presents Little Spirit: Christmas in New York". The animated TV special is about a friendly New York cab driver (Danny DeVito) who tells a magical story to two sisters (Song and Rachel Shier). The television special received five million viewers. In late 2008, Song made a special appearance at the grand opening of the RTA HealthLine in Cleveland.
In early 2009, Song started filming Boogie Town with Marques Houston and Vanessa Simmons. The film is compared to West Side Story; it is set in a future New York City where dancing battles occur in "Boogie Town". In the film, Micah (Houston) falls in love with Natalie (Song), the sister of the head of a rival dance group, and the two become a modern Romeo and Juliet. The film was shot in downtown Los Angeles. Distributed by Vivendi Entertainment, it was scheduled to be released in the summer of 2009, but it was postponed, and was expected to be released theatrically in 2010.
In October 2009 Song joined the main cast of Columbia Pictures' The Social Network alongside Jesse Eisenberg, Andrew Garfield and Justin Timberlake. The film was about the founders of the popular social networking site, Facebook. Song portrays Eduardo Saverin's girlfriend. The film won the "Hollywood Ensemble Award" from the Hollywood Awards and was nominated for eight Academy Awards, including Best Picture.
An independent film starring Song, Little Sister, was announced at the 2010 Cannes Film Festival in May 2010. The film is distributed by Goalpost Film and Goalpost Productions. In 2012, Song filmed a pilot for a TV series called Table for Three.
In 2012, Song guest starred as Alissa in the TV show Scandal. She worked on a pilot with ABC for Table for Three. Song has been working on a movie with actress Brittany Snow called 5 More. As announced in November 2012, Song will be joining the cast of New Girl as a recurring character portraying Daisy. Song has been represented by the International Creative Management and Richard Konigsberg Management.
In 2005, an article "Maths Spotlight on... Brenda Song" in Scholastic Math included facts about Song and mathematical guidance from her. Song appeared alongside Paula Abdul and several other celebrities in a "Our Time to Vote" commercial, which aimed to encourage American citizens to vote during the 2008 presidential election. In 2009, Song participated in the "Diet Pepsi Easter Holiday House" event. She decorated an egg at the event that was sold in an online auction benefiting Feeding America.
According to Time, Song is one of the three Disney starlets who have not been involved in the Hollywood party girl scene, along with Hilary Duff and Raven-Symoné. Asiance Magazine calls her a "great role model" for young girls. She said in 2005, "Besides Hollywood grand-openings and award shows, I try to stay away from the parties. It’s so easy to be swept away from that whole scene because it’s expected of you. I’ve never drank or smoked in my entire life, but I’ve seen 15-year-olds drinking and smoking and I just think that’s gross." On being a young role model to kids, Song said: "Oh goodness, I hope I can set a good example. If I can do it, anyone can. I’m living my dream every single day."
On October 14, 2011, People reported that Song was engaged to Trace Cyrus. On June 11, 2012, Cyrus announced that the couple had ended their relationship.