Born in Blacktown, New South Wales, Fifita is of Indigenous Australian and Tongan descent. Fifita began playing rugby league with twin brother David in the Penrith junior rugby league system before moving to Griffith, New South Wales. He attended Patrician Brothers' College, Blacktown and Wyndham College. He played junior football for the Doonside Roos, St Patricks Blacktown and the Griffith Waratahs.
As a teenager, Fifita trialled with the Sydney Roosters and the North Sydney Bears, but was considered lightweight, even though he was playing as a winger or centre at the time. Fifita said he, "tried eating and all that stuff but it didn't work and then one day I just blew out. It wasn't until I was 17 or 18 that I put the size on. Maybe it was the grog, I don't know. I was seriously pushing to get to 80kg back then. I think I was about 70kg." Fifita would eventually sign with the Wests Tigers and later played in their NYC team in 2009, including playing at prop in the 2009 NYC Grand Final against the Melbourne Storm in the 22-24 loss.
His twin brother David also played lower-grade for the Tigers. Fifita is not related to John Fifita, a former St George Dragons player. Fifita's elder brother Latu Fifita plays for Workington Town in the Kingstone Press Championship.
In round 2, Fifita made his first grade debut for the Wests Tigers against Sydney Roosters, coming off the interchange bench where he scored a try in the 44-32 loss at the Sydney Football Stadium. In round 23, against the Penrith Panthers, Fifita scored two tries in the Tigers 43-18 win at Campbelltown Stadium. Fifita finished his debut year in the NRL with 5 tries from 22 matches. On 25 October, Fifita made his international debut for Tonga, starting at prop in the 6-22 loss against Samoa at Parramatta Stadium. Fifita commented after match saying, "It was a good experience, it's not about the loss here, it's about the experience and about looking forward to the future for the World Cup and the years ahead."
Fifita was chosen to participate in a New South Wales developmental squad. In the off-season he had dropped about 10 kilos to be playing at about 109 kg. Fifita started the season at prop, but was dropped from first grade by Tim Sheens after round 19 and never returned. "I was always saying, 'Let me play, let me play,'" Fifita said. "But he just said go to NSW Cup. I was pulling 80 minutes each game there, what can you do? You're up against the coach. You can't say anything. At the end I had kind of given up. I thought there was no more first grade for me." On 15 July, Fifita signed with the Cronulla-Sutherland Sharks on a 3-year deal, starting from 2012 after was released from the Wests Tigers, along with Bryce Gibbs, so that the club could accommodate Adam Blair under the salary cap. Fifita finished his last year with the Wests Tigers with 3 tries in 17 matches.
On 9 February, Fifita played for the Indigenous All Stars against the NRL All Stars, starting at prop in the 28-36 loss. In round 1, Fifita made his debut for the Cronulla-Sutherland Sharks against his former club, the Wests Tigers, playing off the interchange bench in the 16-17 loss at Leichhardt Oval. In round 4, against the North Queensland Cowboys, Fifita scored his first club try for the Sharks in the 20-14 win at 1300SMILES Stadium. With the Sharks starting 2012 well, and with his old club struggling to win early games, Fifita commented, "We have an unbelievable bond. We're so tight. Compared to the Tigers everyone is so tight. We have the same dressing rooms. It's just more of a friendship. We're all just brothers and it's no split groups, no nothing, it's who we are." Fifita finished his first year with the Sharks with him playing in 22 matches and scoring 5 tries.
On 9 February, Fifita played for the Indigenous All Stars against the NRL All Stars, starting at prop in the 32-6 win. Fifita proved to be a revelation for the Sharks in the 2013 NRL season and was rewarded with representative selections for NSW City Origin and the New South Wales State of Origin teams. On 21 April, he played for City Origin against the NSW Country Origin side, where he played off the interchange bench and scored a try in the 12-18 loss. On 5 June, Fifita made his State of Origin debut for New South Wales against Queensland, where he played off the interchange bench in the Blues 14-6 win at ANZ Stadium. Despite NSW losing the series 2-1 to Queensland, Fifita drew rave reviews for his powerhouse performances in the series. After continuing his good form for the Sharks and helping them to a 5th-place finish, Fifita was selected as the 2013 Dally M Prop of the year after being the Sharks highest tryscorer with 9 tries from 25 matches.
Fifita was chosen in the 24-man Australian squad for the 2013 Rugby League World Cup. On 26 October, he made his international debut for Australia against England where he played off the interchange bench in the 28-20 win at Millennium Stadium. In his third match for Australia, against Ireland, Fifita scored his first international try in the Kangaroos 50-0 win at Thomond Park. In the Kangaroos semi-final match against Fiji, Fifita scored the last try of the match in the 64-0 win. It was the last try ever described by BBC rugby league commentator Ray French. During the tournament, Fifita played in 6 matches and scored 2 tries for Australia, including playing off the interchange bench in the Kangaroos 34-2 World Cup win over New Zealand at Old Trafford.
On 11 March, Fifita signed a four-year contract worth more than $800,000 a season to play with the Canterbury Bankstown Bulldogs. On 31 March, Fifita's contract with the Canterbury-Bankstown Bulldogs was terminated. A statement from the Bulldogs stated that they had advised Fifita's management that he would not be playing for the club "given the final terms of the NRL Playing Contract could not be agreed." On 26 April, Fifita re-signed with Cronulla on a four-year deal until the end of the 2018 season. Fifita later made public the terms of the memorandum of understanding he had signed, which stated he would be paid $800,000 per season. When the official contract was received 17 days later, the figures were much lower, and only offered $375,000 for the first season. On 4 May, Fifita played for City against Country where he scored a try in the 26-all draw. In round 9, against the Parramatta Eels, Fifita suffered an ankle injury. The injury resulted in Fifita missing the 2014 State of Origin series, and a big chunk of the NRL season. Fifita returned in round 18, against the Newcastle Knights. In round 22, against the New Zealand Warriors, Fifita suffered a broken arm which ended his season. Fifita played in 12 matches during his tumultuous heavily publicised 2014 NRL season.
On 17 August, Fifita was involved in a road rage incident at Taren Point where he allegedly threw an object at a car travelling behind him and later after the pair pulled over, Fifita allegedly got out of his Jeep and verbally abused the 23-year-old male driver of the Subaru before punching and kicking the panels of his car.
In round 2, against the Brisbane Broncos, Fifita played his 100th career match in the Sharks 2-10 loss at Shark Park. On 3 May, he played for City Origin in the 22-34 loss in Wagga Wagga. Fifita's good form in the early rounds of the season earned him a spot back into the New South Wales Blues team, where he played in game 1 of the series, coming off the interchange bench in the Blues 10-11 loss at ANZ Stadium. He wasn't selected for games 2 or 3.
On 6 August, Fifita and his twin brother David were given 6-week suspensions and a $30,000 fine after they abused a referee at a junior match in Penrith. The pair allegedly abused the referee because a player in the team they were helping out, St Patrick's Blacktown, was injured in back play and the referee didn't stop the match. During the suspension, on an episode of The Footy Show, Fifita discussed how he had suffered severe depression in October 2014 and attempted suicide by trying to hurl himself out of a 20th story window at a holiday resort at Surfers Paradise after a drunken night out with his brothers and friends celebrating a friend's bucks night. Fifita revealed that he had been saved when someone in the room grabbed his legs and pulled him back inside and said "David punched me in the face, punched me in the mouth, I sat there laughing at him", I was just yelling at him 'I don't care: it's over, do what you want.' Life was over for me at that point." Fifita had become suicidal amid the pressures of his team's poor results, a personal form slump and complications involving his contract. Following the incident, Andrew's brother David forced him to see seek psychiatric help after which he received treatment for depression and a personality disorder. After his suspension was over, Fifita returned for the Sharks in their elimination finals match against the reigning premiers the South Sydney Rabbitohs, where he played off the interchange bench in the Sharks 28-12 win. Fifita finished the year with him playing in 18 matches and scoring 7 tries for the Sharks.
On 13 February, Fifita played for the Indigenous All Stars against the World All Stars, starting at prop in the 12-8 loss at Suncorp Stadium. On October the 2nd, Fifita played for the Cronulla Sharks against the Melbourne Storm in the 2016 NRL Grand Final, which the Sharks won 14-12 at ANZ Stadium in Sydney. He scored the winning try with ten minutes to go in the game, carrying several defenders over the line with him.
On 31 May 2017, Fifita played for the New South Wales Blues in game 1 of the 2017 State of Origin series and was instrumental in the team's 28-4 win over the Queensland Maroons. He fended multiple times to put James Maloney in under the posts, then made some runs. He took advantage of a loose ball from Justin O'Neill to score under the posts. Fifita was adjudged man of the match.