In 1982, Barry McGuigan won eight fights, seven by knockout. One of the fights almost destroyed his career and his life. He was faced on June 14, 1982, with Nigeria's Young Ali. McGuigan won by a knockout in six rounds, and Ali fell into a coma, from which he never recuperated, dying six months later in his homeland. According to the book The Ring Boxing The 20th Century, McGuigan has declared that he wasn't sure he wanted to keep on being a boxer after that fight.

However, he did continue boxing, and in 1983, he won four fights, including his first trip to fight outside Europe (when he beat Samuel Meck by a knockout in six in Ontario, Canada), before getting his first try at a title. On November 16, Italy's Valerio Nati defended his European Featherweight belt versus McGuigan in Belfast, and McGuigan won the crown with a knockout in the sixth round. He then became the number one Featherweight challenger in the World Boxing Association.

In 1984, he won five bouts, all by knockout. Among the fighters he beat were former world title challengers Jose Caba and Felipe Orozco. He also beat fringe contender Paul DeVorce to keep his chance at a Word Championship attempt alive.

In 1985, McGuigan met former world Featherweight champion Juan Laporte and won by a decision in the tenth round. Following one more win, he finally got his world title try when the WBA world featherweight champion, Eusebio Pedroza, came to London to put his title on the line against McGuigan. McGuigan became a world champion by dropping Pedroza in round seven and winning a unanimous fifteen round decision. McGuigan instantly became a national hero, and earned promotional deals such as a video game named Barry McGuigan Boxing, which won critical acclaim (awarded a "Sizzler!" in Zzap64). Later that year, he was named BBC Sports Personality of the Year.

McGuigan made his first defense against Bernard Taylor, who was stopped in the ninth, and then against Danilo Cabrera, who got knocked out in fourteen rounds. This proved to be a controversial stoppage: The fight was stopped after the challenger bent over to pick up his mouthpiece after losing it, a practice that is allowed in many countries but not in Ireland. Cabrera was not aware of this, and the fight was stopped. Although Cabrera's corner protested the outcome, McGuigan remained the winner by a knockout.

For his next defense, he went to Las Vegas in June of 1986, where he faced the relatively unknown Stevie Cruz from Texas in a fifteen round title bout. McGuigan held a lead halfway through, but suffered dehydration because of the extreme heat, and wilted near the end, being dropped in rounds ten and fifteen. He eventually lost a fifteen round decision and the world belt. After the fight, McGuigan required hospitalization because of his dehydrated state.

After that fight he retired, partly due to the death of his father in 1987. He used to say his father was his greatest inspiration and after his death he apparently felt there was no reason to continue boxing. However, he returned to the ring between 1988 and 1989, beating former world title challengers Nicky Perez and Francisco Tomas Da Cruz before losing to future challenger Jim McDonnell by a Technical knockout in four rounds(Cuts). After that fight, he retired permanently from boxing. In the 1980s he was a chat show host on BBC1.

His record was 32 wins and 3 losses, with 26 wins by knockout. In January 2005, McGuigan was elected into the International Boxing Hall of Fame.