Laila Ali won the IBA title with a second round knockout of Suzette Taylor on August 17, 2002, in Las Vegas. On November 8, she retained that title and unified the crown by adding the WIBA and IWBF belts with an eight round TKO win over her division's other world champion Valerie Mahfood, in Las Vegas. Ali stopped a bloodied Mahfood in eight rounds. On June 21, 2003, Mahfood and Ali fought a rematch, this time in Los Angeles. Once again bloodied by Ali, Mahfood lost by TKO in six rounds while trying to recover her world title. Nevertheless, Ali suffered a bad cut on her right eyelid for the first time in her career, inflicted by Mahfood. Ali also suffered a bloodied nose for the second time in her career during this fight, the first being in Ali's fight with Frazier-Lyde two years previously. On August 23, 2003, Ali fought her original inspiration, Christy Martin, beating Martin by a knockout in four rounds. On July 17, 2004, Ali retained her world title, knocking out Nikki Eplion in four rounds.

On July 30, 2004, she stopped Monica Nunez in nine rounds, in her father's native city of Louisville, Kentucky. This fight was part of the undercard for the fight in which Mike Tyson was surprisingly knocked out by fringe contender Danny Williams. On September 24, 2004, Ali added the IWBF light heavyweight title to her resume by beating Gwendolyn O'Neil (whom she had earlier canceled a fight against) by a knockout in three rounds, at Atlanta, Georgia. On February 1, 2005, in Atlanta, Ali scored a commanding and decisive eighth round technical knockout over Cassandra Geiggar in a ten round fight.

On June 11, 2005, on the undercard to the Tyson-Kevin McBride fight, Ali defeated Erin Toughill in round three to remain undefeated and won the World Boxing Council title in addition to defending her WIBA crown. She was the second woman to win a WBC title (Jackie Nava was the first). Toughill and Ali disliked each other, and prior to the fight Toughill joked about Ali. Ali promised she would punish Toughill, much like her father did with Ernie Terrell back in 1967. On December 17, 2005, in Berlin, Ali fought and defeated Asa Sandell by TKO in the fifth round. Following Ali's hard right to Sandell's face with 17 seconds remaining in round 5, Sandell was struck by numerous undefended shots to her head. The referee stopped the bout with 12 seconds remaining. Muhammad Ali was in attendance and kissed his daughter.