Bruno became a professional boxer in 1982, quickly achieving 21 consecutive wins by knockout. This streak caught the attention of international boxing magazines, such as The Ring, KO Magazine, Boxing Illustrated and Ring En Español. During this period Bruno defeated former world title contender Scott LeDoux, the fringe contender Floyd Cummings, Belgian champion Rudy Gauwe, British contenders Tony Moore and Eddie Nielson, and opponents such as Bill Sharkey, Walter Santemore and Ken Lakusta. However, in May 1984 the up-and-coming future world heavyweight champion, American James "Bonecrusher" Smith, halted that streak when he defeated Bruno by knockout in the tenth and final round of their bout, with Bruno leading clearly on all three judges' cards. As a general view, Bruno was carefully managed, whereby he developed well to later give a strong account of himself in the big matches.
Bruno won his next six bouts against respected opposition. He won the European heavyweight title with a KO over Sweden's Anders Eklund, KO'd former European champion and world title contender Lucien Rodriguez in one round, was taken the distance for the first time by the useful world rated Phil Brown, and beat fringe fighters Larry Frazier and Jeff Jordan.
Bruno got back into title contention with an impressive one-round KO win over former WBA champion Gerrie Coetzee of South Africa, and, in July 1986, he challenged Tim Witherspoon for the WBA heavyweight title. 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.
Bruno once again got himself back into title contention with wins over former contender James Tillis and journeymen Reggie Gross and Chuck Gardner. In October 1987 Bruno faced the veteran Joe Bugner in an all British match up. Bugner although long past his peak, was coming off impressive wins over Greg Page, James Tillis and David Bey. Bruno won by TKO in the 8th round, the referee stopping the bout, although it appeared the protesting Bugner could have continued.
In February 1989, Bruno challenged Mike Tyson for the undisputed world heavyweight title. In the opening moments, the fighters came together with huge punches. Bruno's legs buckled, and he took a big step back, inadvertently stepping off the ring apron. Most agree that he would have gone down, at least to a knee in any event, and this was called a knockdown. Bruno did not complain, and instead gathered himself to continue, ultimately rocking Tyson (for the first time in Tyson's career) with a left hook toward the end of the round. However, Tyson recovered and eventually beat Bruno when the referee stopped the contest in round five with Bruno taking heavy punishment, lying helpless on the ropes.
Bruno kept winning fights, helping him to retain his spot as one of the world's leading heavyweights. He defeated contender Carl Williams, and then journeymen such as Jose Ribalta, Pierre Coetzer, and Dutchman Jan Emmen.
In 1993 he had a third world title chance against young Lennox Lewis, who was making the second defence of the belt (his first of three championship reigns). The Lennox Lewis vs. Frank Bruno fight was the first time that two British boxers had fought for the world heavyweight title. Lewis beat Bruno on a stoppage in round seven, Bruno again failing to take his title chance after leading the contest on points up until what proved the final round.
Bruno again regrouped, dispatching trialhorse Jesse Ferguson in one round, and the fringe contenders Rodolfo Marin and Mike Evans equally easily.
On 2 September 1995, Bruno finally became world champion by outpointing WBC Champion Oliver McCall over twelve rounds. Bruno did not last long as champion – the contract he signed to get McCall meant he had to face Mike Tyson in his first defence. Tyson beat Bruno on a stoppage in round three, Bruno performing unusually poorly in what turned out to be his last bout as a professional, due to a severe eye injury caused by Tyson. Bruno was advised not to fight again to avoid running the risk of causing any more damage to it, which could result in permanent blindness. Bruno retired soon after the fight.
Bruno's publicist throughout most of his career was sports historian Norman Giller, who wrote three books in harness with Frank: Know What I Mean, Eye of the Tiger and From Zero to Hero. His manager for all but his last five fights was Terry Lawless, who signed him as a professional shortly after he had become ABA heavyweight champion at the age of eighteen.
Bruno grew up with five siblings in Wandsworth, South West London. His mother was Jamaican and his father was Dominican. In 1990, Bruno married his partner Laura at a small church in Hornchurch, an area of Greater London near the border with Essex. They had two daughters: Nicola and Rachel, and a son, Franklyn. However, their relationship deteriorated, and they divorced in 2001.
On 22 September 2003, Bruno was taken from his home near Brentwood in Essex by medical staff assisted by police officers, under the provisions of the Mental Health Act 1983. He was taken to Goodmayes Hospital in Ilford, where he underwent psychological and psychiatric tests. He had been suffering from depression for several months beforehand. He was later diagnosed as having bipolar disorder. On 9 October 2005 he admitted that his cocaine use, which began in 2000, contributed to his mental health problems. Media coverage of Bruno's problems raised controversy, the principal accusations being gross intrusion and insensitivity. Particular criticism was aimed at The Sun, whose headline in the first editions the next day read "Bonkers Bruno Locked Up". Second editions retracted the headline and attempted to portray a more sympathetic attitude towards Bruno and mental health in general. As an attempt at atonement, the paper established a charity fund for people suffering from mental illness, although some mental health charities condemned The Sun's latter action that day as being grossly cynical in the light of the former. On 24 February 2008, Bruno offered his support to former footballer Paul Gascoigne, who on 21 February had been sectioned under the Mental Health Act. Bruno also spoke on his own personal experiences in the mental health system at a conference run by Hari Sewell, on 22 June 2009. In December 2013, Bruno spoke to the Daily Mirror in support of their mental health campaign, stating: "Mental illness is a terrible thing to have to cope with but I’ve learnt it’s a fight you can win if you live your life the right way".
In December 2005, Bruno announced that he was to become a father for the fourth time since finding new romance with old friend Yvonne Clydesdale. The pair, who first met five years previously at a health resort, began dating months after bumping into each other at a wine bar near his home. Yvonne gave birth to baby Freya on 10 May 2006. On 10 October 2006, Bruno and Clydesdale were jointly awarded £50,000 damages for libel against The People newspaper and publishers MGN in respect of false claims made about their relationship.
In 2006, Bruno published an autobiography Frank: Fighting Back. It won the Best Autobiography category of the British Sports Book Awards.
Bruno's image was enhanced by his relationship with the BBC boxing commentator Harry Carpenter, his appearances on the early Comic Relief programmes in the 1980s and his frequent appearances thereafter on television and on stage (in pantomime).
In 1991, he opened "The Ultimate" at Lightwater Valley which was, at the time, the longest roller coaster in the world. He described the ride "scarier than Mike Tyson".
In 1995, the year of his world championship, he released a cover version of "Eye of the Tiger", the theme song of the movie Rocky III. It reached No. 28 in the UK charts. In 1999, he featured on the celebrity special in the second season of Fort Boyard.
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 Member of Parliament, Martin Bell. His proposed slogan was "Don't be a plank, vote for Frank!" However, this idea was quickly dismissed by Conservative Central Office. But in an interview with BBC Sport at the time Bruno laughed at the story and denied he had any intention of standing.
In 2006, he was one of a number of celebrities who were recorded on the World Cup song, "Who Do You Think You Are Kidding Jurgen Klinsmann?".
On 15 August 2009 he appeared on The Weakest Link beating Duke McKenzie in the final for £12,800. He had a small role in the 2008 British crime drama Cass. Bruno made brief guest appearances in episodes of the ITV comedy show, Harry Hill's TV Burp in February and October 2011. On 21 April 2011, Bruno appeared on the ITV1 chatshow The Alan Titchmarsh Show, where he was candid about his previous health issues. In 2011, he made a guest appearance in Sooty. On 20 April 2012, Bruno was featured in the ITV series Piers Morgan's Life Stories.
He supports West Ham whilst also having an affinity for Aberdeen.
Bruno completed the 2011 London Marathon which is the third marathon he has run successfully. He has also run numerous half marathons. He is also a patron for The Shannon Bradshaw Trust, a children's charity. Bruno regularly makes personal appearances and also sells autographed items of memorabilia.
On 23 July 2013, Bruno was featured in the BBC Three documentary with his daughter Rachel in Rachel Bruno: My Dad and Me.