Despite being a talented athlete as a teenager, Caulker chose to pursue a career in football playing his early football with Hounslow Borough, his local club. After initially playing as a central midfielder, he acted on advice from a coach and made the switch to central defence. After a single match at centre back for Hounslow at the age of 15, he was offered trials with seven clubs including Tottenham Hotspur, Chelsea, Reading and Queens Park Rangers. Caulker joined the Tottenham Hotspur youth team and having broken into the Under-18s team as an Under-16 player during the 2007–08 season, Caulker progressed to make 31 appearances and scored one goal in 2008–09. He also forced his way into the reserve team that season, making five appearances, and captained the Under-18s towards the start of that season. He impressed during his first season as a full-time scholar and signed his first professional contract at Tottenham in July 2009.

In July 2009, Caulker went on loan to League One club Yeovil Town along with teammate Ryan Mason. He made his league debut at the start of the 2009–10 season against Tranmere Rovers, where Yeovil won 2–0. After impressing in Yeovil's 0–0 draw with Oldham, Caulker made the Football League Team of the Week. Along with fellow Tottenham loanees Ryan Mason and Jonathan Obika, on 5 November 2009 his loan extended until the end of the 2009–10 season. On 1 March 2010, Caulker was included in the Team of the Week for a second time following the 1–0 home win against MK Dons. Caulker returned to Spurs one match early after starting 44 of Yeovil's 45 league matches, having missed only one match due to playing for England U19s also taking four of Yeovil's five end of season awards. In November 2013, he was selected to be part of Yeovil Town's 'Team of the Decade', which was voted for by the club's fans to commemorate their tenth season as a Football League club. Caulker was the only loan player to be chosen.

Caulker received his first call-up to the England U21 squad for the friendly against Germany on 16 November 2010. He made his debut in that match, coming on as a 77th-minute substitute for Martin Kelly in a 2–0 defeat. In February 2011 Caulker was called up to the England U20 squad for their friendly against France but withdrew after an injury. Caulker was named in the 31-man U21s squad for two warm-up matches for the 2011 U21 European Championship with friendlies against Denmark and Iceland but had to pull out through injury and missed both matches, and the treatment of this injury caused Caulker to miss out on a call-up to the 40-man provisional squad for the 2011 European Championship. Caulker was recalled to the U21s team for the double-header matches against Azerbaijan and Israel, in September 2011. and featured in both matches. On 13 January 2012, Caulker was named on Stuart Pearce's shortlist for the 2012 Summer Olympics Great Britain Olympic football team. Having been watched by Fabio Capello during Swansea's 3–2 victory over Arsenal, Caulker was tipped for a call-up to the England squad for their friendly against the Netherlands, in an attempt to tie his Future down to England due to his eligibility for Scotland. On 23 February 2012, Caulker was called up for England U21s' 2013 European Championship qualification match against Belgium. Caulker started and scored his first international goal in a 4–0 victory on 29 February 2012.

On 5 November 2011, Caulker was arrested for a public order offence after an incident in Swansea city centre. He was issued with a fixed penalty notice and later released. Caulker later revealed that his arrest was for swearing in the street and apologised to the club and his manager Brendan Rodgers for getting caught-up in the late night offence.

On 8 November 2012, Caulker received his second call up from Roy Hodgson to the England national football team for the friendly against Sweden. Caulker started the friendly against Sweden on 14 November and scored a debut goal when he turned in a Steven Gerrard free kick from the right from three yards out. He played the first 74 minutes before being substituted with England winning 2–1, the team eventually losing 4–2.

In November 2013, Scotland assistant manager Mark McGhee confirmed interest in Caulker, who has a grandmother from the country. As his only England cap was a friendly, he is permitted to change allegiances.

On 22 July 2014, Caulker transferred to Queens Park Rangers for an undisclosed fee, signing a four-year contract. He scored his first goal for the club in a 2–2 home draw against Stoke City on 20 September. Caulker left Queens Park Rangers by mutual consent on 28 December 2017.

On 29 July 2015, Caulker joined Premier League club Southampton on a season-long loan. He made his debut for Southampton in the second-leg of their Europa League third qualifying round match against Vitesse Arnhem, on 6 August 2015. Caulker only made eight appearances for Southampton, the last of which came in a 6–1 home defeat by Liverpool on 2 December 2015.

Caulker's loan with Southampton was cancelled on 12 January 2016 to allow him to join Premier League club Liverpool on loan until the end of the season. Caulker made his Liverpool debut on 13 January 2016 in the 3–3 draw with Arsenal at Anfield when he replaced Adam Lallana as an auxiliary striker in the 87th minute. For the next two league matches, home against Manchester United and away against Norwich City, he entered the match as striker in the 90th minute, contributing to the 95th-minute winner by Adam Lallana in the latter.

In June 2017, Caulker was interviewed by The Guardian and discussed his problems with alcohol, gambling addiction and depression. Caulker acknowledged that his problems had damaged his football career and had led him to consider suicide.

In February 2018, Caulker signed a one-and-a-half-year deal with Dundee. He scored on his debut for Dundee in a 3–2 loss at Kilmarnock on 13 February 2018. In April 2018, Dundee rejected a club-record bid for Caulker from Norwegian champions Rosenborg.