He made his Premiership debut for Exeter Chiefs on 25 November 2012 in a 27–23 win over London Irish. After establishing himself as a regular in the Chiefs first team, Nowell was nominated for, and won, the LV=Breakthrough Player Award for the 2012–13 season.

Nowell represented England at Under-18 and Under-20 level. He scored in the 2013 IRB Junior World Cup final win over Wales.

On 1 August 2013, he was selected in the England Saxons squad on the advice of chief scout Andy Fairley.

On 9 January 2014, Nowell was included in the England squad for the 2014 Six Nations Championship, after numerous injuries. He made his debut for England in the 26–24 defeat to France, despite a difficult start to the game Nowell made the most metres by any England player in the game (87 metres). He scored his first try for England during the 52–11 win over Italy. Nowell missed the 2014 summer tour of New Zealand due to injury.

In 2016 Nowell was part of the Exeter Chiefs side to reach the Aviva Premiership Final, eventually won by Saracens, after finishing second in the overall table and winning a home semi-final against Wasps.

Nowell started all five of England’s RBS Six Nations matches in 2016 where England won the Grand Slam. He scored a try in the opener against Scotland. Nowell also was part of the successful 3–0 series win over Australia in 2016 starting the second and third test and acting as a replacement in the first and scoring a try from the bench. Nowell played despite having a thumb injury for which he missed the opening few rounds of the 2016–17 domestic season.

In 2017 Nowell produced a try-scoring performance in the Aviva Premiership Final, as Exeter Chiefs claimed their maiden Premiership title.

In April 2017, Nowell was called up for the British and Irish Lions, becoming the first player to be called up from the Exeter Chiefs.