Born in Exeter, Devon, Ampadu is a product of the Exeter City youth academy. On 9 August 2016, aged 15 years 10 months and 26 days, he made his debut in a EFL Cup first round match against Brentford at St James Park, playing the full 120 minutes of a 1–0 victory. He became the club's youngest ever player, breaking an 87-year-old record set by Cliff Bastin, and being named man of the match. A week later, he made his league debut in a 1–0 home defeat against Crawley Town in EFL League Two

On 1 July 2017, Ampadu signed a contract with Premier League club Chelsea. The two clubs had entered negotiations over a compensation fee for the player in an attempt to reach a fee that both found acceptable for the then 16-year-old. Yet, in November 2017, Exeter City chairman Julian Tagg said that, whilst there was still a positive relationship between the two clubs, there was also a "massive disparity" in both clubs' valuation of the player.

On 20 September, Ampadu made his debut for Chelsea in an EFL Cup third round match against Nottingham Forest, coming on in the 55th minute for Cesc Fàbregas. Doing so made him the first player born in the 2000s to play for the Chelsea senior team. At 17 years and six days old, he also became the youngest player to debut for the Blues in over ten years. On 12 December, he made his Premier League debut for Chelsea, coming on as a substitute against Huddersfield Town in the 80th minute.

Ampadu plays internationally for the Wales national football team. He was also eligible to represent England, Republic of Ireland and Ghana.

On 26 May 2017, at the age of 16, Ampadu was called into the senior Wales squad ahead of their World Cup qualifier with Serbia. He was called up again on 1 November for friendlies against France and Panama, and made his debut on 10 November at the Stade de France, coming on as a 63rd-minute substitute for Joe Ledley in a 2–0 defeat to the French.