He was given his first-team debut by George Burley at the age of 16 on the opening day of the 2003–04 season in a 3–0 home defeat to Stoke City, where he was voted Man of the Match. Though Derby struggled in Huddlestone’s first full season, Huddlestone was one of Derby’s few bright points, with Burley saying “He’s a terrific talent. As a young player, he (is) the best passer of a ball I (have) ever seen, and I’ve worked with some good young players.” He eventually went on to appear in 43 of Derby’s 46 league matches that season. He enjoyed an equally successful 2004–05 as Derby reached the First Division play-offs, where they lost to Preston North End in the semi-final. However, halfway through the season Huddlestone signed for Premier League club Tottenham Hotspur in January 2005 for a fee reported to be worth up to £2.5 million, though he remained at Derby for the rest of the season. He had made a total of 95 appearances for Derby, without scoring.

Huddlestone spent a few months of the 2005–06 season on loan to Wolverhampton Wanderers, scoring his first league goal, at Derby, before returning to make his debut for Tottenham as a substitute in the 1–0 defeat away at Fulham on 31 January 2006.

His first start for Tottenham came on 14 September 2006, away to Slavia Prague in the UEFA Cup, a match that Tottenham won 1–0. His first goal for Tottenham came in the League Cup fourth round match against Port Vale on 8 November 2006. Huddlestone scored two goals in this match, his second goal proving decisive in extra time, taking Tottenham through to the quarter-final of the competition. Huddlestone got his first league goal for Tottenham on 17 December 2006 against Manchester City with an excellent half-volley on 24 minutes, hit first-time after assisting with teammate Calum Davenport’s first goal with a free-kick. Huddlestone established himself as one of the most promising young English central midfielders in the Premier League towards the end of the 2006–07 season and head coach Martin Jol compared Tom Huddlestone with German legend Franz Beckenbauer due to his playmaking abilities, ferocious shot power and versatility.

On 25 December 2006, he signed a new four and a half-year contract – keeping him at the club until 2011. Tom signed a new and improved five-year contract on 30 June 2008 committing his future to Tottenham until 2013. He came on as a substitute as Tottenham beat Chelsea in the 2008 League Cup Final at Wembley Stadium. During the 2009–10 season, he became a regular under Harry Redknapp. In March 2010, he extended his contract until 2015. Huddlestone was plagued with injury during the 2011–12 season and managed only four appearances for the club. Huddlestone returned for the 2012–13 season and made his first appearance as a substitute for Jermain Defoe against Norwich City on 1 September 2012. He was shown a red card for serious foul play, the match ended in a disappointing 1–1 draw. The red card was later rescinded.

Having been capped at the U-17 and U-19 levels, Huddlestone was a regular in the England under-21s. He played twice in the 2007 UEFA European Under-21 Championship before a red card for dissent ruled him out of the semi-final and final. In October 2008, he scored the opening goal from a free kick in the second leg of the 2009 UEFA European Under-21 Championship qualification play-offs against Wales. Although the match ended in a draw which ensured qualification for England, it was marred by his sending-off in the second half for a reckless challenge on Darcy Blake. He missed the tournament through injury.

He was called up into the England squad for the first time by coach Fabio Capello to face the United States and Trinidad and Tobago in friendlies. On 14 November 2009, he received his first cap for the senior team in the 1–0 loss in a friendly against Brazil, after coming on as a substitute in the 81st minute. His next appearances came in a 2010 FIFA World Cup warm up match against Mexico, where he came on in as a substitute in the 61st minute. His latest appearance for England also came in a World Cup warm-up match against Japan where he started for the first time in 2–1 victory.

In May 2010, Fabio Capello announced that Huddlestone would be in his preliminary World Cup squad of 30 players. However, was not selected for the final 23-man squad. On 11 November 2012, new England manager Roy Hodgson gave Huddlestone his first call up to the squad for two years for a friendly match against Sweden on 14 November.

Shortly after scoring a goal for Tottenham against Arsenal in April 2011, Huddlestone accepted a challenge not to cut his hair until he scored again, to raise money for charity. It took him two-and-a-half years, and 55 matches, before he finally scored his next goal (in a Premier League match for Hull against Fulham on 28 December 2013), and he raised more than £57,000 for Cancer Research UK as a result.

On 14 August 2013, Huddlestone moved to Hull City for an undisclosed fee believed to be about £5.25 million. He made his debut on the first day of the 2013–14 season when he came off the bench in a 2–0 loss away at Chelsea. On 28 December, he scored his first goal for Hull in a 6–0 home win against Fulham, his first goal since April 2011. On 28 January 2014, Huddlestone acted as emergency goalkeeper after Hull City’s goalkeeper Allan McGregor was sent off for squaring up with Crystal Palace’s player Stuart O’Keefe. With Hull already making three substitutions, Hull’s manager Steve Bruce ordered Huddlestone to take over the goalkeeping role.

On 13 April 2014, he scored Hull’s third goal in their 5–3 FA Cup semi-final victory over Sheffield United at Wembley Stadium. On 17 May 2014, Huddlestone started in the 2014 FA Cup Final against Arsenal at Wembley Stadium, in which Hull were beaten 3–2 after extra time.

On 1 July 2016, he signed a new two-year deal with the club.

On 15 July 2017, Huddlestone returned to boyhood club Derby County, by signing a two-year contract, with an option of a third season, for an undisclosed fee, believed to be around £2 million. He scored his first goal for Derby in a 3–0 home win against Brentford on 3 February 2018, more than 14 years after his debut for the club.

On 1 July 2020, Huddlestone revealed that he and Derby County had failed to agree a contract extension and he would be leaving the club.