O’Loughlin’s dad, Keiron, and uncle, Kevin, both played more than 250 games for Wigan in the 1970s. His father Keiron O’Loughlin also featured in the 1983–84 Challenge Cup Final for the Widnes side which achieved victory over Wigan. It was the Wigan-based amateur club Wigan St Patricks which gave Sean his first experience of competitive rugby league. He had already gained international experience as part of the 2001 Great Britain Academy of Australia, a product of the Wigan academy, for whom he started playing in under-19s matches in 2001, and continued to do so in 2002. During his time at the academy, O’Loughlin played in a variety of positions, including a game against Wakefield Trinity in the senior academy championships where he played at Centre scoring two tries, and another against Hull Kingston Rovers where he scored a try playing at Second-row.

In 2002, he also featured in two matches during the cross-code Middlesex Sevens tournament, playing at Scrum-half in a team composed of both Wigan and Orrell R.U.F.C. players. Because of this, O’Loughlin remains one of only a handful of rugby league players ever to play at Twickenham, the home of English rugby union, along with those in the St. Helens, Bradford Bulls and Huddersfield teams who competed in the 2001 and 2006 Challenge Cup finals. He is the Uncle of current England rugby union captain Owen Farrell, and the Brother-in-Law of current rugby union coach Andy Farrell.

On that night, O’Loughlin played at Loose forward, which eventually became his usual position, but during his first season he played in no less than three positions. After returning from the Middlesex Sevens event where he played Scrum-half, he made another starting appearance against Warrington, this time at Stand-off. He also started, and scored a try, at Centre against Leeds. O’Loughlin’s first season mostly saw him come into the match as an interchange, starting in only five of the twenty-one appearances he made throughout the league season. Also in 2002 he was named as captain of the England A squad that faced New Zealand in November and later toured Fiji and Tonga. He made 3 appearances on the tour and was sent off and sin-binned in the same match against Fiji. He was named captain of the 2003 England A squad to face Australia and in the European Nations Cup. He also gained his first senior representative honour when he represented Lancashire in the 2003 Origin match.

O’Loughlin played for the Wigan Warriors at stand-off half back in the 2003 Super League Grand Final which was lost to Bradford Bulls. O’Loughlin played loose forward for most of 2004 with Andy Farrell moving to prop as cover for injuries. During the season he earned a new contract and a call up to the Great Britain squad for the first time for the 2004 Tri-Nations series. He made his début off the bench against Australia, and his first starting appearance in the following match against New Zealand.

After making an impressive start to the 2005 season, he suffered a serious knee injury in the Good Friday derby against St Helens, ruling him out for the rest of the season. He returned to the first team in 2006 and was announced as captain by coach Ian Millward. The poor start to the season left Wigan bottom of the Super League and led to the sacking of Ian Millward who was replaced by Brian Noble.

O’Loughlin showed a dramatic improvement under Noble. His performance in 2006 earned him a recall into the Great Britain squad for the mid season international with New Zealand at Knowsley Road, St. Helens which Great Britain won. Also at the end of season he was selected in the squad for the 2006 Tri-Nations in Australia, playing in Great Britain’s opening defeat by New Zealand but playing an important role in Great Britain’s victory over Australia. He missed Great Britain’s 34–4 defeat by New Zealand with a muscle strain.

With O’Loughlin’s contract expiring at the end of 2006 he was linked with a move to new Australian NRL side Gold Coast Titans for most of the season but in November 2006 he signed a new two deal with Wigan keeping him at the club until 2008. O’Loughlin was forced to rule himself out of contention for the England training squad for the 2008 Rugby League World Cup through injury. Likewise he was forced to withdraw from the 2009 Four Nations England squad before the start of the series.

The 2010 season saw O’Loughlin noted for his hard work rate, topping most if not all stats. He has been the player of the month twice in 2010 and been in the Super League dream team a record 7 times in total (up to 2018). He was selected to play for England against France in the one-off test.

He played in the 2010 Super League Grand Final victory over St. Helens at Old Trafford.

O’Loughlin captained Wigan in the 2011 Challenge Cup Final victory over Leeds Rhinos at Wembley Stadium, playing at loose forward, helping defeat Leeds 28–18.

O’Loughlin played for England in the 2013 Rugby League World Cup. The following year, following the international retirement of Kevin Sinfield, he was named as England captain ahead of the Four Nations tournament.

He played in the 2014 Super League Grand Final defeat by St. Helens at Old Trafford.

He played in the 2015 Super League Grand Final defeat by Leeds Rhinos and the 2016 Super League Grand Final victory over the Warrington Wolves, both at Old Trafford.

In 2015 he was named the captain of England’s squad for the end-of-year test series against New Zealand. Beforehand there was a test match where England took on France. Sean O’Loughlin was the captain of the team that went on to demolish Les Tricolores. O’Loughlin scored tries in the first match of the New Zealand test-match series in Hull and the decisive third match in Wigan. He was an influential captain throughout the series, leading his side to England’s first series victory in 8 years. His influential performance also resulted him in winning the George Smith Medal as player of the series.

In 2016, O’Loughlin was sent off for the first time in his career for a high tackle on Wakefield’s Chris Annakin. He was subsequently given a one-match ban by the disciplinary tribunal.

He played in the 2017 Challenge Cup Final defeat by Hull F.C. at Wembley Stadium.

In October 2017 he was selected in the England squad for the 2017 Rugby League World Cup.

He played in the 2018 Super League Grand Final victory over Warrington at Old Trafford.

In November 2019, O’Loughlin signed a new one-year contract with the club, and announced that he would be retiring at the end of the 2020 season.