Dougie Imrie, Ali Crawford, Mickael Antoine-Curier, Tony Andreu and Daniel Redmond were all on target to give Hamilton their biggest top-flight win since 1938.
Accies struck after just eight minutes when Imrie strode onto a throughball and powered his shot past Dan Twardzik.
Motherwell tried to get back into the game with Henrik Ojamaa trying his luck from 25 yards but ‘keeper Michael McGovern watched the ball slither past the post after deflecting off a defender.
Imrie went close to netting a second when Twardzik had to scramble across his goal as the shot went narrowly wide.
The home side extended their lead after 29 minutes when Twardzik had to deal with a fierce Andreu drive, but he could only parry the ball into the path of Crawford and he hooked the rebound into the roof of the net.
Hamilton almost grabbed a third goal in the dying seconds of the opening half when Crawford found Antoine-Curier in the box but he crashed his shot just over the crossbar.
The hosts continued to dominate after the break and Antoine-Curier hit the post with a side-footed shot from 12 yards after good work by Crawford.
Antoine-Curier then strode into the Motherwell box and he kept his composure before slotting home on 64 minutes.
Crawford was involved yet again when he cut the ball back for Andreu who dispatched his shot with ease five minutes later to make it 4-0
Motherwell’s best chance came shortly after the fourth goal, when Ojamaa smashed a shot across McGovern and inches wide of the far post.
Substitute Redmond completed the rout with three minutes remaining when he prodded home from close range.
Hamilton were following up their 4-0 victory at Fir Park in late September as they inflicted a first defeat on new Motherwell manager Ian Baraclough after wins in his first two games in charge.