Clottey rebounded from the controversial loss by winning the African Boxing Union welterweight title in his next fight. He then rolled off a 10 fight winning streak highlighted by his first win on American soil and capture of several minor welterweight and middleweight titles. The streak culminated in an IBF intercontinental welterweight title. On December 2, 2006, Clottey earned his first shot at a world title but broke his hand in the fourth round of his fight against World Boxing Organization champion Antonio Margarito. That bout against Margarito has since come under controversial suspicion following news reports (released after Margarito's fight with Shane Mosley) that Margarito had boxed opponents with hand wraps illegally loaded with plaster (along with Margarito's first bout with Miguel Cotto). On April 7, 2007 (following Clottey's questionable loss to Margarito), Clottey earned a unanimous decision over Diego Corrales, in what was Corrales's final fight before his death. In December 2007, Clottey positioned himself for another title shot with a win over prospect Shamone Alvarez. Clottey beat Zab Judah on August 2, 2008, for the IBF welterweight title vacated by Antonio Margarito.

On June 13, 2009, Clottey faced Miguel Cotto in New York City at Madison Square Garden for the WBO welterweight title. Cotto dropped Clottey in the first with a jab. Cotto was cut in the third round by an accidental head butt. Clottey's combinations throughout the fight gave Cotto problems. Cotto emerged the winner with a controversial split decision.

Clottey fought seven-division world champion Manny Pacquiao on March 13, 2010 in Arlington, Texas, at the Dallas Cowboys Stadium following the disagreement on terms of a proposed boxing match between Manny Pacquiao and Floyd Mayweather Jr. which would have been scheduled on the same date in Las Vegas, Nevada. Clottey lost to Pacquiao by unanimous decision. Pacquiao threw a total of 1231 punches in the fight, missing 985 and landing 246. Clottey threw a total of 399 punches, 291 missed and 108 hit Manny. On November 19, 2011, after over a year away from the ring, Clottey returned to defeat Calvin Green via TKO in the second round. Since then however, Clottey confirmed that he'd retired from boxing to care for a sick relative.

In mid-2013, Clottey announced his return to boxing, saying he had been inactive because of managerial problems. Clottey returned to the ring on September 14, 2013, when he faced Dashon Johnson. Clottey made easy work of Johnson, showing no ring rust whatsoever en route to winning a dominant and wide unanimous decision. On April 9, 2014, Clottey went on to beat former middleweight champion Anthony Mundine, dropping Mundine five times. Clottey was in line to fight Canelo Alvarez later that year, but the fight never materialized, partially to do with an injury to Canelo's ankle. In late 2015, Clottey faced fringe contender Gabriel Rosado at a 158 lb catchweight, despite having success and leading early in the fight, Clottey was outworked over ten rounds. He lost a unanimous decision and has not fought since.

Clottey rose to prominence by winning his first twenty fights, including 14 by knockout. His performance set him up to fight Carlos Baldomir, in a title defense by Baldomir for the WBC international welterweight title. Clottey was winning until the 10th round, where he was penalized two points for an intentional head butt. After another clash of heads, Clottey was disqualified.