Ferguson was a member of the female trio Wild Orchid, which she fronted with Stefanie Ridel and fellow Kids Incorporated star Renee Sandstrom. Wild Orchid released two albums, but after completing a third album, their record label declined to release it, and she left the group shortly thereafter. Her disappointment with Wild Orchid led to an addiction to crystal methamphetamine. In September 2006, Ferguson talked with Time about quitting her crystal meth addiction. "It was the hardest boyfriend I ever had to break up with," she says. "It's the drug that's addicting. But it's why you start doing it in the first place that's interesting. A lot of it was being a child actor; I learned to suppress feelings."

In 2003, the Black Eyed Peas were recording their third album, 2003's Elephunk, when will.i.am invited Ferguson to try out for a song called "Shut Up". She got the gig and instantly bonded with the trio to record five additional songs on the album.

In the following spring, shortly before Elephunk came out, Interscope chairman Jimmy Iovine had offered Ferguson a permanent spot to take over vocal duties and fill the spot left void by background singer Kim Hill, who had left the group in 2000. When will.i.am was asked to sum up his bandmates, he called Ferguson the "body" of the group.

In 2005, Ferguson inadvertently urinated on stage during a performance at San Diego's Street Scene festival. Ferguson later commented on the incident: "I had a few drinks before the show, but I didn't think to go to the bathroom before we went onstage. We were jumping around...and my bladder just started."

After two successful Black Eyed Peas albums, Ferguson began pursuing a solo career. She recorded two songs for the Poseidon soundtrack and performed "Auld Lang Syne" in the film. Her first album, released on September 19, 2006, was entitled The Dutchess. The album's name is a misspelled variant of the former title of Sarah Ferguson, the Duchess of York, with whom Ferguson shares a surname and popular nickname. The solo deal does not mean Ferguson is leaving the Black Eyed Peas, as she intends to remain with the group, alternating between the two duties. The album is similar in style to that of the Black Eyed Peas, as fellow Peas member will.i.am is the album's executive producer.

The Dutchess spawned six hits for Ferguson, beginning with "London Bridge", "Fergalicious", "Glamorous", "Big Girls Don't Cry" ,"Clumsy", and "Finally". Her second single, "Fergalicious", peaked at #2 on the Billboard Charts. "London Bridge" reached #2 on the United World Chart, while "Fergalicious" and "Glamorous" both made it to #4; the latters all reached #1 in the U.S. "Big Girls Don't Cry" became Ferguson's first worldwide #1 single, and is her most successful single to date. "Clumsy" was announced as the fifth single from The Dutchess after the major international success of "Big Girls Don't Cry". Ferguson scored her fifth consecutive Top 5 hit from The Dutchess after "Clumsy" reached a peak position #5 on the Billboard Hot 100, on December 22, 2007.

Fergie before a Black Eyed Peas concert at East Stroudsburg University of Pennsylvania in 2004.In addition to promoting her albums and singles, Ferguson appeared at Wembley Stadium on July 1, 2007, performing "Glamorous" and "Big Girls Don't Cry" in a concert for the late Princess Diana put on by her two sons Prince William and Prince Harry; the DVD of the concert was released November 5, 2007.

On November 18, 2007, Ferguson won the Pop or Rock "Favorite Female Artist" at the American Music Awards. In addition, her song "Big Girls Don't Cry" also earned Ferguson a Grammy nomination for "Best Female Pop Vocal Performance", which she lost to Amy Winehouse. In December 2007, Blender picked Ferguson as their woman of the year.

During the 2008 broadcast of Idol Gives Back, Ferguson also performed with Ann Wilson of Heart. The two (with Nancy Wilson on guitar) performed "Barracuda".

The song "Labels or Love" was recorded for the Sex and the City movie soundtrack. In an Entertainment Weekly interview, director and writer Michael Patrick King stated that "it’s an entirely new song with lyrics, but it has the Sex and the City theme as the DNA — on steroids.”

Ferguson has also appeared on Nickelodeon's show Dance on Sunset. Ferguson has recently released an EP for download on iTunes featuring unreleased singles. The CD version was released on May 27, 2008.

Ferguson collborated with Japanese singer Kumi Koda on the song "That Ain't Cool". "That Ain't Cool" was featured on Kumi's single "Moon", released on June 11, 2008. The single debuted at #2 on the Oricon Weekly Single Charts. She also performed a "duet" with Michael Jackson (her vocals mixed with Jackson's 1982 recordings), "Beat It 2008" on Thriller 25, the 25th anniversary release of Jackson's iconic album Thriller.