The son of a Nigerian, Igbo father, he was raised in Heaton Moor, Stockport, England, with his two younger sisters by his English mother, attending Stockport Grammar School. Amaechi moved to the United States to play high school basketball at St. John's Jesuit High School in Toledo, Ohio. He began playing college basketball at Vanderbilt but transferred to Penn State, where he was a two-time First Team Academic All-American selection. While at Penn State, Amaechi became a motivational public speaker and a mentor for area youth.

The 6 ft 10 in, 270 lb (208 cm, 122 kg) center was signed undrafted by the Cleveland Cavaliers in 1995. He played 28 games for the Cleveland Cavaliers during the 1995—1996 season, then played for two years in Europe (France: Cholet, Limoges; Italy: Kinder Bologna; Greece: Panathinaikos; UK: Sheffield Sharks). In the season 1996—1997 he played for Panathinaikos BC. In September 1996 he won the Intercontinental Cup, being the first scorer (alongside with Fragiskos Alvertis) of Panathinaikos BC with 59 points in the 3 games of the tournament (18,23,18 pts). In 1997—1998 he played with Kinder Bologna but left mid-season before the Italians won the Euroleague.

He returned to the USA, signing with the Orlando Magic in 1999. With a solid 1999—2000 season, where he averaged 10.5 points in 21.1 minutes per contest, he gained fame for scoring the NBA's first points in the year 2000. Before speaking publicly about being gay, Amaechi may have been best known for turning down a $17 million contract offer from the Los Angeles Lakers in 2000, opting to remain in Orlando for $600,000 per year. Amaechi went on to play for the Utah Jazz from 2001 to 2003.

He was traded to the Houston Rockets midway through his final NBA season in exchange for Glen Rice, and, though he was an active player, he did not participate in any games for them.

Amaechi came out of retirement to represent England during the Commonwealth Games in Melbourne, helping the England national basketball team win the bronze medal. In all he made 18 caps for England.

Amaechi previously worked on coverage of a weekly NBA basketball game on UK television channel Five and provided co-commentary for the BBC at the 2008 Olympic Games. In addition, Amaechi owns Animus Consulting, which provides motivational speakers, and is a partner in Animus Development, an executive training program.

Amaechi is also involved with the ABC Foundation in Manchester, which encourages children to become involved in sports and their communities by building youth sports centers throughout the United Kingdom. The first such facility, the Amaechi Basketball Centre, was built in Manchester, not far from Amaechi's childhood home of Stockport. The venue is also home to the English Basketball League's Manchester Magic (men) and Manchester Mystics (women), both of which are owned by Amaechi.

In a radio interview, Amaechi said that he is returning to school to get a Ph.D. in psychology. "I want to do something more meaningful in my life," he said. Amaechi also explained why he played for Orlando in 2000 for much less than the $17 million offered to him by the Lakers; his answer was that Orlando had hired him in 1999 when no other team would. "There are many people who are asked what their word is worth, and when people ask me that I can say, 'At least $17 million.'"

In February 2007, Amaechi spoke about his homosexuality on ESPN's Outside the Lines program. He also released a book, Man in the Middle, published by ESPN Books (ISBN 1933060190), which discusses his career and life as a closeted professional athlete. Amaechi is the first NBA player to speak publicly about being gay.

Few male team sports members in the United States have come out as gay. Among them are former NFL players Esera Tuaolo, Roy Simmons, and Dave Kopay, and former Major League Baseball players Glenn Burke and Billy Bean. Bean wrote an op-ed in support of Amaechi's decision.

Cyd Zeigler, the co-founder of Outsports.com, a website dedicated to the gay influence in sports, said, "I don't think (Amaechi's declaration) will have any effect on his ability to do that," referring to Amaechi's businesses and charitable work. "You will have some people who will raise an eyebrow," Zeigler added.

Zeigler said he has read an advance copy of Amaechi's book and spoken with him on the telephone. He gave some insight to Amaechi's upbringing in England, where he was raised by his mother and felt isolated because of his size and mixed race.

In a 2002 interview with Scotland on Sunday, Amaechi had previously spoken about gays in the NBA: "If you look at our league, minorities aren't very well represented. There's hardly any Hispanic players, no Asian-Americans, so that there's no openly gay players is no real surprise. It would be like an alien dropping down from space. There'd be fear, then panic: they just wouldn't know how to handle it."

In May 2007, a few months after coming out, Amaechi said he had "underestimated America", adding that he had expected the "wrath of a nation" but it never materialized. He made these statements despite having been the subject of death threats a few months earlier.

In August 2008, Amaechi was sent to Beijing to do Olympic Men's and Women's Basketball broadcasts and reporting for the BBC. There, he authored a blog with fellow activist and renowned photographer Jeff Sheng in partnership with Amnesty International. He used Sheng's knowledge of Mandarin and experience in Beijing to get behind the scenes and gather candid interviews with locals and Olympic athletes alike.

In 2008, John Amaechi made several appearances on Shirts & Skins, a reality series on LOGO Television. Amaechi acted as team "mentor" and "psychologist" to the San Francisco Rockdogs, a gay basketball team, and shared his experiences on basketball, life, and coming out. Skins & Skins: Episode 2 In 2010, Amaechi made public that he had been denied entry to a gay bar in Manchester, allegedly because the doorman felt he was "big, black and could be trouble". He is considering legal action.

Amaechi is a patron of LGBT History Month UK.

Reaction from other players

One widely-publicized response to Amaechi's announcement came from former NBA player Tim Hardaway, who stated that he would ask for a gay player to be removed from his team: "First of all I wouldn't want him on my team. Second of all, if he was on my team I would really distance myself from him because I don't think that's right and I don't think he should be in the locker room when we're in the locker room. Something has to give. If you have 12 other ball players in your locker room that's upset and can't concentrate and always worried about him in the locker room or on the court or whatever, it's going to be hard for your teammates to win and accept him as a teammate." Hardaway later apologized for his remarks.

Some players gave Amaechi public support: former Magic teammate Grant Hill said "the fact that John has done this, maybe it will give others the comfort or confidence to come out as well, whether they are playing or retiring." Shaquille O'Neal told the New York Daily News, "If he was on my team, I guess I would have to protect him from the outsiders, I'm not homophobic or anything. I'm not the type who judges people, I wish him well." Charles Barkley said "It shouldn't be a big deal to anybody. I know I've played with gay players and against gay players and it just shouldn't surprise anybody or be any issue."

However, the prevailing public statements from NBA players tended to toward an expression of mixed feelings on the matter. Steven Hunter said that he would accept an openly gay teammate "as long as he [didn't] make any advances toward me. As long as he came to play basketball like a man and conducted himself like a good person, I'd be fine with it." That sentiment was echoed, though less tactfully, by Shavlik Randolph, who said that "as long as you don't bring your gayness on me I'm fine. As far as business-wise, I'm sure I could play with him. But I think it would create a little awkwardness in the locker room." Pat Garrity warned that an openly gay player could expect to face both acceptance and hostility from his teammates. He said that "they would have teammates that would accept them for being a good person and a good teammate, and there would be people who would give him a hard time about it. I think that's true if you're playing basketball or in an office job. That's just how the world is right now." LeBron James felt that he couldn't trust a gay teammate who was in the closet, saying "with teammates you have to be trustworthy, and if you're gay and you're not admitting that you are, then you are not trustworthy. So that's like the No. 1 thing as teammates ... we all trust each other.... It's a trust factor, honestly. A big trust factor."

John Amaechi was awarded an Honorary Degree of Doctor of Science by Manchester Metropolitan University on July 19, 2007 in recognition of his achievements not only as an athlete and broadcaster, but also for his charitable work with the National Literacy Trust, the NSPCC and the establishment of the ABC Foundation to encourage children to become involved in sport and their community.

Amaechi was a judge on the BBC Series The Speaker in 2009.