On 20 January 2018, Nelson made his Premier League debut in a 4–1 win against Crystal Palace, coming on as a substitute in the 72nd minute. On 8 April 2018, he made his first Premier League start in a 3–2 win over Southampton, being substituted off in the 64th minute for Jack Wilshere. On 17 May 2018, Nelson was awarded the PL2 Player of the Year.
On 31 August 2018, Nelson signed a long-term contract with Arsenal, then went on season-long loan at German club 1899 Hoffenheim for a loan fee of €500,000. On 15 September 2018, he made his debut as a 72nd-minute substitute away to Fortuna Düsseldorf, and within 14 minutes of entering the field of play, Nelson scored for Hoffenheim, scoring a consolation goal for the club in a 2–1 loss. Reiss had an impressive sophomore season for Hoffenheim, scoring 7 goals in just 587 minutes of action at such a young age.
In March 2018, Nelson scored twice for England under-19 against Hungary in a qualifier for the 2018 UEFA European Under-19 Championship. He was one of a number of players withdrawn from selection for the tournament by their club.
On 11 October 2018, Nelson made his U21 debut against Andorra, coming on as a second-half substitute; he scored the Young Lions' sixth goal with a backheel in stoppage time in a 7–0 victory that secured qualification for the 2019 UEFA European Under-21 Championship.