A six-game losing run left the bottom-of-the-table Yellow-Blues on 16 points with four games left to play this weekend, 12 points adrift of 15th-placed Emmen and 16th-placed Excelsior in the relegation playoff spot.
Cambuur therefore needed to win on Saturday night and hope for a miracle in the coming weeks to keep any wafer-thin hopes of survival alive, but their fate has now been sealed.
Sjors Ultee's men fell behind to Sander van de Streek's header in the 37th minute, before Golden Boot-chasing Anastasios Douvikas also nodded home four minutes later to leave Cambuur with the steepest of mountains to climb.
Douvakis scored his 16th top-flight goal of the season from the penalty spot in the 64th minute to consign Cambuur to second-tier football for the 2022-23 season, ending their brief two-year stay in the big time.
Cambuur can now only finish on a maximum of 25 points this season and only have the consolation prize of 17th place to fight for, with Groningen - who could also be demoted later this weekend - one point better off than the Yellow-Blues.
After a five-year spell in the Eerste Divisie, Cambuur were promoted to the Eredivisie in 2020-21 and finished ninth last term during a respectable first season back in the top flight, but they have only won four of their 31 games during a disastrous campaign this time around.