Nwaneri came on for Fabio Vieira in the 90th minute as Mikel Arteta's men cruised to a 3-0 win at the Brentford Community Stadium. Vieira had earlier struck a superb goal in his first start for the club, while William Saliba and Gabriel Jesus were also on target as Arsenal moved back to the top of the table.
At 15 years, 5 months and 23 days, Nwaneri broke the record previously held by Liverpool's Harvey Elliott (16 years, 30 days). In doing so, the midfielder became Arsenal's youngest-ever senior player, breaking the record held by Cesc Fabregas (16 years, 5 months and 24 days).
Arsenal manager Mikel Arteta said: "It's another step, another experience. In your career all the steps are not going to be forward. After that maybe he needs three backwards to go another forward, but I think he deserved it. It sends a really strong message about who we are as a club as well.
"I told him yesterday that he was going to be with us and that I want him to experience how it is to be in the hotel, to do a preparation of the game to be around the boys and that he had to be ready. If you're going to be on that bench you have to be ready. The boy just looks in your eyes and he's ready.
"All the decisions that we take and that I take are for the club. It's not for me, it's not for the player, it's because we believe that he has a talent that has to be developed incredibly in the next two or three years. We will see how we manage that but the boy will dictate. Normally it's not us, normally the players tell you and demand of you how far you can go on that."
Nwaneri's appearance marks the latest step in a promising career at Arsenal, where he has broken into the club's under-21 set-up and also represented England at U16 level.
The youngster wasn't born when Arsenal's Emirates Stadium opened in 2006.