Powell has represented England at under-16, under-17, under-18, under-19 and under-21 levels. On 5 November 2009, he made his debut for the under-16 team in a 2–0 win against Northern Ireland. On 25 August 2010, Powell made his debut against Turkey for the under-17 side. On 28 August 2010, Powell scored a free-kick for the under-17s in a 4–0 win against Australia in the FA Men's under-17 International Tournament. He played in the 2011 UEFA European U-17 Football Championship, with England making it to the semi-final and Powell scoring against France in the group stage. Powell made his under-18 debut in a 3–0 win against Poland on 7 March 2012 at Crewe's Alexandra Stadium. He scored on his under-19 debut against Germany on 6 September 2012. He was called up to the under-21 squad for the first time on 3 October 2012, for the play-off games against Serbia. He made his debut on 13 November, playing the full 90 minutes of a 2–0 win against Northern Ireland at Bloomfield Road.
Born in Crewe, Cheshire, Powell started his career at home-town club Crewe Alexandra, joining their youth system as a five-year-old. He made his debut for Crewe on 19 August 2010, in a League Two game against Cheltenham Town, which ended in a 3–2 defeat at Whaddon Road. At the age of 16 he came on as a second-half substitute for Clayton Donaldson, becoming the second youngest player ever to appear for Crewe.
On 20 August 2011, after only being on the pitch for eight minutes, Powell was sent off for the first time in the 2–0 defeat to Shrewsbury Town, following a poor challenge on Terry Gornell. Powell scored his first senior goal in a 3–1 away win at AFC Wimbledon on 15 October 2011. In January 2012, Powell was awarded the Football League's Young Player of the Month Award for December. He scored his first brace against Gillingham in a 4–3 win on 10 March 2012. On 21 April 2012, he won every award at Crewe's end of season awards ceremony, becoming the first player to win all five, including Goal of the Season (for his 30-yard strike in the 4–3 win at Gillingham), Young Player of the Year and Player of the Year.
Powell played his first match for United on 21 July 2012 coming on as a second-half substitute in a pre-season friendly against Ajax Cape Town in South Africa. Four days later, he made his first start for Manchester United in a pre-season friendly match against Shanghai Shenhua. He made his Premier League debut against Wigan Athletic in a 4–0 win on 15 September 2012, coming on as a substitute for Ryan Giggs in the 71st minute, and scoring his first goal for United in the 82nd minute after receiving a pass from Javier Hernández.
On 2 September, he was loaned to newly promoted Premier League team Leicester City for the rest of the season, with Tom Lawrence also making the move but on a permanent basis. On 1 November, Powell made his Leicester debut against West Bromwich Albion in the Premier League, coming on as a second-half substitute for Danny Drinkwater on 81 minutes in a 0–1 home defeat. On 27 December, it was reported that Leicester City had opted to terminate Powell's loan early due to the player showing a lack of commitment to training.
Powell was given the number 22 for the 2014–15 season. He started the first game of the season in a League Cup match against Milton Keynes Dons which United lost 4–0. He was later substituted for James Wilson.
Powell was included in United's Champions League squad for their crucial group game against VfL Wolfsburg on 9 December 2015, due to a number of injuries. He came on as a replacement for Juan Mata in this game which United went on to lose 3–2. PSV knocked Manchester United out of the Champions League, defeating CSKA Moscow in the other Group B match. He also came on as a second-half substitute in United's next game, a league defeat at Bournemouth, his first league appearance for United in over three years.
On 12 July 2016, Powell returned to Wigan Athletic on a free transfer, signing a three-year contract. On 13 August 2016, Powell scored in his first appearance of the season, in a 3–0 home win against Blackburn Rovers. His first season was seemingly ended prematurely by injury during a January 2017 FA Cup game against Nottingham Forest, but Powell returned to first-team action three months later, coming on as a substitute and scoring an injury-time winner against Rotherham. On 13 April 2017, Powell scored an 11-minute hat-trick for Wigan, who were 2–0 down in the second half against Barnsley, earning his side a 3–2 home win. Powell continued his scoring momentum four days later, netting from the bench in Wigan's 2–1 away defeat to Brighton & Hove Albion on 17 April 2017. Despite scoring five goals in three consecutive substitute appearances, Powell's exploits weren't enough to help Wigan avoid relegation to EFL League One.
Powell opened his account for the 2017–18 EFL League One campaign on 5 August 2017, scoring from close range in Wigan Athletic's 1–0 opening day victory at Milton Keynes Dons. Powell claimed a second-half brace the following week, scoring a header and converting a penalty as Wigan cruised to a 4–1 home win against Bury.
In April 2018 he was nominated for the EFL League One Player of the Season award.
