Bruno became a professional boxer in 1980, quickly racking up a streak of 20 consecutive wins by knockout. This streak caught the attention of many international boxing magazines, such as Ring Magazine, KO Magazine, Boxing Illustrated, The Ring En Espanol and many others. In March of 1984, however, future world Heavyweight champion, American James Bonecrusher Smith, then a boxing journeyman, halted that streak when he defeated Bruno by knockout in the tenth and final round of the bout, with Bruno leading on all three judges' cards.
Bruno got back into title contention with wins over the likes of former WBA world champion Gerrie Coetzee (by knockout in round one), and, in July of 1986, he challenged Tim Witherspoon for the WBA world Heavyweight championship. After once again leading on the cards for most of the fight, he ran out of steam and was defeated by knockout, in round eleven.
In 1989, Bruno, whose training partners included celebrities like Sting, challenged Mike Tyson for the unified world Heavyweight title. After being sent down in round one, Bruno finished that round by rocking Tyson with a right. However, Tyson beat Bruno by knockout in round five.
Frank Bruno kept winning fights and he kept his spot as one of the world's leading Heavyweights, and in 1993, he had a third chance, against young Lennox Lewis, who was making his second defense of his first of two championship reigns. Lewis beat Bruno by knockout in round seven.
In September, 1994, Oliver McCall beat Lewis in London, and, after defeating Larry Holmes, he went to England to defend the WBC title against Bruno. Bruno finally became world champion by outpointing McCall over twelve rounds.
Bruno did not last long as champion: his first defense was a rematch with Tyson. Tyson beat Bruno by knockout in round three, in what turned out to be Bruno's last bout as a professional.
Bruno grew up with five siblings in a terraced house in south London, where his parents had settled after moving to England from the Caribbean. In 1990, he married his partner Laura at a small church in Hornchurch, an area of Greater London near the border with Essex. They had three children. However, their relationship deteriorated, and they divorced in 2001.
In January 2001, Bruno announced that he wanted to stand as the Conservative candidate in the traditionally safe Tory seat of Brentwood and Ongar against the independent MP Martin Bell. However, this idea was quickly dismissed by Conservative Central Office.
On September 22, 2003, Bruno was taken from his home near Brentwood in Essex by medics, assisted by police officers, under terms of mental health legislation. He was taken to Goodmayes Hospital in Ilford, where he underwent psychological tests. He had been suffering from depression for several months beforehand. The psychologist Professor Cary Cooper expressed the opinion that the end of Bruno's boxing career, the breakdown of his marriage, and the suicide of his former trainer George Francis in 2002 all contributed to his condition. Media coverage of the situation raised controversy, with the media being accused of insensitivity.