On June 2001, Gallen made his NRL debut for the Cronulla Sharks against the Parramatta Eels in round 15 at Toyota Park. Cronulla lost the match 36 to 6. He made one more appearance that season in the final round, where the Sharks were victorious over the Brisbane Broncos 24–16.

During the round 11 match (in 2003) against the Newcastle Knights, Gallen was sent off by referee Paul Simpkins after a high shot on Sean Rudder. Gallen made a total of 17 first-grade appearances for the club in 2003, scoring five tries in the process.

In the 2004 season, Gallen made a total of 19 appearances for the club and scoring five tries.

Gallen was presented the Cronulla Sharks chairman’s Award in 2005 by the club’s President Barry Pierce after his impressive season where he led the NRL in both hit ups and off loads. At the 2005 Dally M Awards, he was also nominated for the position of “Best Lock”. However, he lost out to Manly lock Ben Kennedy.

In the 2005 NRL season, Gallen played a total of 25 games in first-grade for the Sharks and in the process scored six tries.

Gallen ran 3,920 metres with the ball in 2005, more than any other player in the competition.

In September 2006, just days after he was voted the Sharks supporters player of the year, Gallen announced that he was considering leaving the Sharks despite having a year left on his contract. Gallen stated that it wasn’t the club or coaching staff that made him consider leaving the club but rather the fact that “I just want to play semi-final football”. Gallen also stated that he was “looking for a fresh start and a fresh challenge”.

In 2006, Gallen made 18 appearances in first-grade for the Cronulla Sharks, scoring seven tries for the club.

Gallen was selected for all three games of the 2011 State of Origin series, as well as for Australia. He scored his first try of the season in round 3, against the Panthers. The Sharks won that game 44–12. In State of Origin II Gallen was controversially selected to play prop and became the first prop to play 80 minutes in an Origin match since Steve Price (rugby league) in 2007. His performance earned him man of the match. Subsequently, there were claims that his performance was fueled by performance-enhancing substances, with journalist Andrew Webster linking these in an article; “State of Origin 2016: The tough question NSW Blues captain Paul Gallen does not want to answer”.

In 2008, Gallen represented Australia in the centennial test, scoring a try.

In August, Gallen was named in Australia’s preliminary 46-man Kangaroos squad for the 2008 Rugby League World Cup, and in October 2008 he was selected in the final 24-man Australia squad.

Although the Cronulla Sharks sat on the bottom of the 2009 NRL ladder after six rounds, Gallen was named in the preliminary 40-man squad for NSW for 2009’s State of Origin series. He was selected for Australia in the one-off test match against New Zealand on 8 May 2009.

In May 2009, Gallen attracted public outrage for racially abusing Mickey Paea. The incident gained attention initially, due to the angry reaction of Paea, who is normally a quiet reserved player with strong religious beliefs. After the event, there were reports Gallen would be stripped of his captaincy. However, pre-empting this, on 1 June 2009, Gallen voluntarily stepped down from his Sharks captaincy.

In December 2009, Paul Gallen was issued with an infringement notice for urinating in public near the head of a drunken friend.

For the 2010 ANZAC Test, Gallen was selected to play for Australia at lock forward in their victory against New Zealand. Gallen was left out of the first match of the State of Origin side but was selected for the two remaining matches. In the second game he was placed on report for a high shot on Nate Myles in the twenty-third minute. However, his performance was still impressive enough to lead Daily Telegraph Sports editor-at-large, New South Welshman Phil Rothfield, to postulate, that of all the NSW players, Gallen “possibly” would be the only one that Queensland would select if he was theoretically available for them (in place of Ashley Harrison). In the last match of the series, Gallen scored his side’s first try just before half time and set up teammate Kurt Gidley for their second try just after the interval.

2011 later emerged as the year of Cronulla’s supplements saga

On 3 November 2011, the annual RLIF Awards dinner was held at the Tower of London and Gallen was named lock forward of the year.

Gallen began his amateur boxing career in 2012 in part of a rugby league versus rugby union charity event in Auckland, New Zealand. It was announced he would fight New Zealand international rugby union player Hikawera Elliot. Gallen received a three-round unanimous points victory over Elliot on debut. The following year Gallen prepared for his second amateur fight against another fellow New Zealand international player Liam Messam. He defeated Messam in a split decision over three two-minute rounds in Auckland.

Gallen was selected for Australia in the 2013 ANZAC Test and played at lock forward. In what was the first test match ever played in Canberra, New Zealand were defeated. Gallen was named captain of the New South Wales Blues for the 2013 State of Origin series. Gallen led his team to victory in game one at ANZ Stadium in Sydney, however the win was not without controversy, and Gallen lodged a guilty plea to a striking charge for the undefended punches he landed on the head of Maroons forward, Nate Myles. Gallen had not been sent off for the infringement and this led to the introduction of a rule that players would be sin-binned for any punch thrown in future Origin matches.

From 2013 until 2015, Gallen was a panelist on SportsFan Clubhouse alongside Renee Gartner and Mieke Buchan and hosted by Bill Woods. The show was a sports program that at aired on 7mate.

On 22 August 2014, Gallen was one of the Sharks players who pleaded guilty to having unknowingly used banned peptides, and in exchange was given a reduced, backdated ban from ASADA and Sports Minister Peter Dutton for his part in the 2011 supplements scandal. Gallen received nearly $80,000 from the NRL to cover legal fees, however, in late October, Gallen sent an offensive tweet aimed at the NRL, complaining of a lack of support to him regarding the issue. It was later deleted and replaced with a story which Gallen attempted to blame his father, which Gallen admitted lying about before taking responsibility.

On the even of The 2014 state of origin series, Gallen labelled Queensland fans as “Two Heads”. Speaking at the 2014 team announcement, Gallen said “If you take it as it comes, and you enjoy the part of it and enjoy going up there and listening to what those two heads give you , we have got the job done on the field before and that is where it counts”. Gallen captained the New South Wales team to victory over Queensland in the 2014 State of Origin series. The win marked the first time that New South Wales had won the series during the current decade and it put an end to Queensland’s record of eight series wins in a row.

In 2014, Gallen turned professional after it was confirmed he would fight Australian-based Herman Ene-Purcell on the undercard of Daniel Geale versus Garth Wood. Gallen was awarded a technical knockout victory inside two rounds despite being dropped by a left hand in the first-round.

His next opponent was for the Footy Show Fight Night in January 2015 against Randall Rayment, a current mixed martial arts fighter. Gallen won with a unanimous four-round points win. His fourth fight was another points decision victory over fellow-rugby league forward Bodene Thompson in a charity event at SkyCity Auckland.

Gallen then went on to say “If we got it taken off us, I would throw my ring away and I would quit the club immediately. It wouldn’t sit well with me, The fact is we were under the salary cap in 2016, even with the intended third-party payments. We were under the salary cap. I have no issue with it”.

In 2017, Gallen was named in The City side in the last ever City v Country representative match. On 10 September 2017 Cronulla played against North Queensland in the elimination finals game. Cronulla were expected to win comfortably against a depleted NQ side but found themselves in a tight match at 14-14. With under a minute left, Gallen got within inches of the line for the match winning try but lost the ball. In extra time, Michael Morgan kicked a field goal for North Queensland to make it 15-14 which remained the final score and Cronulla were eliminated from the finals.

In 2018, Gallen became a panelist on Channel Nine’s all new 100% Footy Monday night show. After round 3, Gallen became the first player in NRL History to achieve 50,000 running metres. His closest rival is Billy Slater with 39,439 running metres. Gallen made 21 appearances for Cronulla in 2018 as the club reached the preliminary final before losing to Melbourne 22-6. Gallen did not feature in the match as he suffered an injury the previous week in Cronulla’s victory over Penrith. In October, Gallen signed a one year contract extension to stay at Cronulla for the 2019 season. The deal will make him the first man to play 19 consecutive seasons with an NRL club.

On 20 December 2018, Gallen agreed to return to the ring to fight former professional rugby league footballer John Hopoate with the match being scheduled for 9 February 2019. Hopoate was knocked out in the second round of the bout. He said afterwards “I got caught by a good punch and I can’t hide from that, I went to sleep and fell over”.

Since 2018, he has appeared on 100% Footy alongside James Bracey and Phil Gould – a rugby league show that airs on Monday nights on Channel Nine. Gallen has appeared sometimes on Sports Sunday and Nine’s Rugby League Coverage.

2019 was also the year that Gallen took over from Scott Prince (166 Losses) as the player with the most losses in NRL history.

On August 21, 2019, Gallen was voted as one of the best players of the decade in the NRL team of the decade announcement which spanned from the 2010 to 2019 seasons. The panel who voted were made up of Premiership-winning coaches Phil Gould, Craig Bellamy, Trent Robinson and Ricky Stuart along with Hall of Famers Peter Sterling, Darren Lockyer, Danny Buderus and Laurie Daley.

Also in August 2019, it had been revealed that he had been offered to join the Newcastle Knights for twice as much as his current salary the previous year at $700’000. Gallen declined the contract offer, explaining that it would have a massive impact on him and his family and that he would want to stay loyal to Cronulla for the rest of his career.