The academy product, who turns 16 in July, was brought on in the 84th minute to replace Gavi.
Mallorca youngster Luka Romero is the youngest player to feature in La Liga when he came on against Real Madrid in 2020, aged 15 years and 219 days.
Yamal, who Barca boss Xavi Hernandez called “fearless”, was included him in the squad for the first time against Atletico Madrid last Sunday.
Betis winger Joaquin, 41, who also featured at the Nou Camp on Saturday, had already made 215 La Liga appearances when Yamal was born.
Barca took the lead when Christensen got on the end of Raphinha’s inswinging cross to head home his first goal for the club from six yards out.
Betis substitute Edgar Gonzalez, who had been brought on for the injured Luiz Felipe, was sent off in the 33rd minute after collecting two yellow cards in quick succession.
Lewandowski scored from a Jules Kounde cross three minutes later to increase the hosts’ lead.
Raphinha added a third before half-time, following a lengthy video assistant referee check after the goal was initially ruled out for offside.
Then in the 82nd minute, Ansu Fati’s cross was turned into his own net by Betis defender Rodríguez to seal the result.