Kettlewell informed Chief Executive Brian Caldwell of his decision on Monday morning, saying the personal abuse aimed at his family had gone too far.
He leaves Motherwell in fifth position in the Scottish Premiership but recently hit a bump in form that includes an active run of three straight losses - most recently a 2-1 loss to St Johnstone - and just one win in his last nine in charge.
"Stuart explained that some of the personal abuse was now affecting his family, to the point where they didn’t wish to attend games," a club statement said.
"As a result, he felt it would be best if he tendered his resignation."
Kettlewell's tenure at Fir Park began in February 2023, during which time he oversaw 92 matches, achieving an impressive 41.3 per cent win rate – the highest for a Motherwell manager since Stuart McCall.
Caldwell expressed his disappointment at Kettlewell's departure, acknowledging his significant contributions to the club:
"He had an exceptional record and has generated an impressive amount of transfer income for the club.
"He has been a critical factor in the development of Motherwell academy graduates, as well as developing young loan players during his tenure.
"When Stuart approached me, I was very disappointed to learn the effect this was having on his family and how he was feeling.
"No manager, player, or club employee, every one of whom gives their all for the club, should feel this way."
Caldwell also emphasised "as a fan-owned, community-driven football club, we will always look after our own".
Assistant manager Stephen Frail will take charge of the team for Sunday's match, with Jon Obika and Richard Foster assisting.