Steve Bruce's side had gone five top-flight matches without winning before Saturday's clash but second-half goals from Mohamed Diame and Nikica Jelavic ended that run.
Bruce has bemoaned Hull's recent inability to hold onto leads after throwing away winning positions against Stoke City, West Ham and Newcastle United already this season.
But they were good value for a win which eradicates the memories of Palace's league double over Hull last term.
Hull made the breakthrough on the hour mark when Diame met Andrew Robertson's superb cross for his third goal since joining from West Ham.
The hosts' maiden league win on home soil of 2014-15 was confirmed in the closing stages thanks to a composed finish from Jelavic, as Hull inflicted a first top-flight defeat on Neil Warnock since returning for a second spell as Palace boss.
Bruce made two changes to his XI with Steve Harper deputising for shoulder-injury victim Allan McGregor in goal, while centre-back James Chester replaced full-back Liam Rosenior in a move back to Hull's previously successful 3-5-2 system.
Hull almost made the breakthrough in the second minute when Ahmed Elmohamady, restored to a favoured wing-back role, crossed from the right and found Jelavic at the back post, but the Croatia striker headed over the crossbar.
Palace had gone into the game with the same XI for a third league outing in succession, but Warnock was forced into a change as Scott Dann appeared to jar his knee in blocking Tom Huddlestone's shot and was replaced by Adrian Mariappa.
The hosts finished the half just as strong and went close after superb interplay between Diame and Abel Hernandez led to the former drilling wide from a tight angle.
Hernandez then turned Robertson's cross wide with the lurking Jelavic perhaps better-placed to apply the finish.
Both of Palace's goals in last weekend's 2-0 win at home to Leicester City came from Jason Puncheon set-pieces.
And the winger's deliveries proved dangerous as Yannick Bolasie and Mile Jedinak headers threatened.
Palace's early second-half pressure waned, though, and Hull deservedly moved ahead in the 60th minute.
The ball was deflected wide to Robertson on the left and his excellent whipped cross was met by Diame who got between the Palace centre-backs to thunder his header past Julian Speroni.
Bolasie tested 39-year-old Harper's reflexes with a stinging 25-yard drive, but Hull made the points safe a minute from time as Jelavic was released by Jake Livermore and kept his cool to move onto his right foot and slot home.
Former Hull defender Damien Delaney had a late header cleared off the line but Hull were ultimately comfortable in registering a first league win at the KC Stadium since April
