Soon afterwards he started as a professional on December 5, 1980 by knocking out Oemer Karadenis in round one at Kampala. Soon after that win, Mugabi moved to London where he became acquainted with boxing promoter Mickey Duff, an expert in boxer marketing who landed Mugabi various fights in England and built his reputation there.

Mugabi won eight fights in Europe and then moved to the United States, setting up residence in Florida. Over time he became a favorite of American tv networks, scoring sensational knockouts of contenders such as Curtis Ramsey, Gary Guiden, former world champion Eddie Gazo, Curtis Parker, Frank The Animal Fletcher, Nino Gonzalez and Earl Hargrove. Because of his ability to fight both at Jr. Middleweight and Middleweight, fans began to talk of the possibility of him challenging either world Jr. Middleweight champion Hearns or world Middleweight champion Hagler. Despite Mugabi being a mandatory contender for some time, a Hearns - Mugabi title match never materialised, as Hearns elected to move to Middleweight to challenge Marvin Hagler.

On his way to becoming the number one contender for the middleweight title of each of the three major sanctioning bodies (WBA, WBC, and IBF),^[1] Mugabi ran roughshod over the division and finished each of his opponents inside the distance. Considering his streak and Hagler's tough battle with Hearns on April 15, 1985, some felt Mugabi had a shot at doing what eleven men before him could not: wresting Hagler's undisputed world middleweight title from him.

The fight between Hagler and Mugabi was set for November 14 of 1985. Due to injury, however, Hagler postponed the fight for four months.

The fight finally came up on March 10 of 1986, and it was the first fight televised by Showtime. Mugabi landed his share of blows to Hagler's head and had the better of the early rounds. The turning point came in the sixth round, when Hagler landed many heavy blows and staggered Mugabi. Mugabi fought back gamely but his early knockout wins left him ill-prepared for a long, tough fight. In the end it was Hagler who came out the victor, with a knockout in the eleventh round. Many boxing fans consider this to have been the toughest contest of Hagler's career.

After his first loss, Mugabi retired to Uganda and ballooned in weight to 190 lbs. In September 1986 he contacted Mickey Duff, stating that he was ready to fight again. Mugabi went down in weight and was given an opportunity by the WBC to win their world Jr. Middleweight title, vacated by Hearns. Once again many fans favored him, this time against Duane Thomas, on December 5 of '86. However, Mugabi suffered a broken eye socket, the consequence of a punch with the thumb of Thomas' glove, in round three and the fight had to be stopped. Mugabi underwent optical surgery the next day to repair his injury.

Discouraged by two consecutive losses, Mugabi gained weight and did not fight for nearly fourteen months. In January 1988, he came back to fight Bryan Grant on the undercard of Mike Tyson's title defence against Larry Holmes. Mugabi won by quick knockout and set off on another knockout winning streak. He became number one contender for the WBC 154 lb title in August 1988 but could not land a fight with then champion Donald Curry. After Curry lost his title in an upset in early 1989, Mugabi was given another opportunity to become world champion by the WBC. On July 8 of that year, Mugabi finally made his dream come true, knocking out Curry's successor Rene Jacquot in round one in Grenoble to become the WBC World Jr. Middleweight champion.

After two first round knockout wins against Ricky Stackhouse and Carlos Antunes, Mugabi, who by this time was having difficulty making the weight limit of 154 lbs, put his title on the line against Terry Norris. When Norris downed the champion for the count with a right to the jaw, Mugabi received the dubious distinction as the second fighter, after Al Singer, to both win and lose a world title by first round knockout when he was defeated by Norris.

Showing resilience, Mugabi resurfaced with two more wins and once again found himself fighting for a world title, facing Gerald McClellan on November 20 of 1991 for the vacant WBO Middleweight Championship. Mugabi once again came out on the losing end, again by a first round knockout.

Mugabi then retired for 5 years and moved to Australia where he still resides and trains fighters. In 1996, he came back for the first of an eight fight comeback, but, apart from beating Jamie Wallace by a 12 round decision at the Gold Coast for the Australian Middleweight title, the comeback was undistinguished. After losing to Glenn Kelly by a knockout in eight on January 16 of 1999, Mugabi finally retired with a record of 42 wins, 7 losses and 1 draw, 39 wins by knockout.

His 26 fight knockout win streak stands as one of the longest knockout streaks ever in boxing.

In a comment posted on "The Sweet Science" blog in regard to the Antonio Tarver-Roy Jones Jr match in St. Petersburg, Florida, Mugabi wrote, "It's great to see that Tampa is still having boxing. I, John, am still sorry for letting my fans down that night. But all champions one day will get beaten. But one day I would love to come and watch some fights in the ring at Tampa. I might bring one of the fighters I train in Australia now."

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