On June 21 2003, Ali retained the title in a rematch with Mahfood, knocking her out in six rounds. It was announced on June 30, that she would fight Christy Martin on August 23. She beat Martin by a knockout in four rounds.

Ali was to begin 2004 by fighting Gwendolyn O'Neil of Guyana at Abuja, Nigeria. The fight was canceled, however, when Ali's camp learned no airline had flights scheduled to Nigeria on the date she wanted to arrive there.

On July 17 of that year, she retained her world title, knocking out Nikki Eplion in four rounds. Ali dropped Eplion four times before the fight was stopped.

Thirteen days later, she stopped Monica Nunez in nine rounds, in her father's native city of Louisville. 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, she added the IWBF Light Heavyweight title to her resume by beating O'Neil (whom she had canceled a fight against) by a knockout in three rounds, at Atlanta, Georgia.

Returning to Atlanta on February 11, 2005, Laila Ali scored a commanding and decisive eighth round technical knockout over Cassandra Geigger in a ten-round fight.

On June 11, 2005, on the undercard to the Tyson-Kevin McBride fight, Laila Ali pounded Erin Toughill into submission 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, Erin joked about Ali. Laila promised she would punish Erin, much like her father Muhammad did with Ernie Terrell back in 1967.

Came the big night, Toughill realized, from round one, that Ali's anger towards her was very real. She also discovered, too late, that Laila's hand speed was too much for her to endure, and from round one, Laila punished Toughill, Erin was pounded on the face and body with quick, lightning shots. By the time the third round came, Erin's face was bleeding profusely, and her clothes carried stains of blood. Laila finished her brutalization of Erin by landing, to the face, approximately 20 consecutive punches. Referee Joseph Cooper then stepped in and ended the fight. The Laila Ali - Erin Toughill match is considered one of the most violent female to female fights in history.

On December 17 2005, in Berlin, Laila fought and defeated Åsa Sandell by TKO in the fifth round, marking her 22nd win. The decision was heavily disputed however, and the audience booed Ali during her post-fight interview.

While a guest on Quite Frankly with Stephen A. Smith on June 7, 2006, Ali announced that she would be making a world tour, and said that she was looking forward to fighting Ann Wolfe on an October 2006 date. The fight with Ann Wolfe never materialized. Instead, on November 11, 2006, Ali fought and defeated Shelley Burton by TKO in the fourth round.

On February 3, 2007 in Johannesburg, Ali retained her WBC and WIBA super middleweight world titles, knocking out Gwendolyn O'Neil at 56 seconds of the first round. Ali headlined the first women's professional boxing match in South Africa. She improved to 24-0 with 21 knockouts

Ali was supposed to fight O’Neil again in Cape Town, on August 5, 2006, but she pulled out amid allegations of fraud. In addition, the local promoter couldn't raise the final $325,000 installment of her $525,000 purse. The South African government is investigating the fraud allegations, according to an exposé in the Cape Times.

Laila did fight O'Neil in February 2007, knocking her out in the first round.