The Ayrshire outfit said “change is required” after a run that yielded eight defeats, with assistant manager Stevie Frail also departing Rugby Park.
Former Partick Thistle head coach Kris Doolan has taken over on an interim basis.
Kettlewell was appointed in the off-season after Derek McInnes agreed to leave Kilmarnock for Hearts.
The 41-year-old began the 2025/26 campaign reasonably, collecting six wins from his first 13 matches in charge.
However, Kilmarnock went on to lose six games in succession, followed by two draws and a further two defeats, leaving them three points above bottom club Livingston, who have a game in hand.
Sunday’s defeat at Aberdeen proved decisive.
Kilmarnock had led at Pittodrie before conceding twice late on, a result that left Kettlewell’s overall record at six wins, eight draws and nine losses.
In a statement, the club thanked Kettlewell and Frail for their efforts during their time at the club and confirmed the decision had been taken after careful consideration.
The board said they believe there is plenty of quality in the squad and had hoped results would turn around.
"Unfortunately, change is now required to serve the best interests of Kilmarnock," they said.
“With an important run of festive fixtures about to get underway, starting this weekend at home to Falkirk, we hope all supporters can stick with us as we aim to get back to winning ways.”