Samson smashed his fifth IPL century, second for CSK in four innings, to power Chennai Super Kings to 207/6 after Mumbai Indians opted to bowl.
In reply, MI collapsed to 104 all out in 19 overs to succumb to their biggest defeat in the IPL.
For CSK, Windies left-arm spinner Akeal Hossain grabbed 4/17 in his third match this season, while Afghanistan left-arm wrist spinner Noor Ahmed showed perfect chemistry returning with 2/23 as CSK returned to winning ways after losing their last match against Sunrisers Hyderabad.
Tilak Varma (37) and Suryakumar Yadav (35) only managed double-digit scores as MI endured a shocking collapse in front of their home fans at the Wankhede.
Earlier, CSK opener and keeper-batter Samson held the innings together with wickets falling at regular intervals at the other end to stay till the end.
Samson hit 10 fours and six sixes in his 54-ball unbeaten knock.
For MI, AM Ghazanfar and Ashwani Kumar bagged two wickets each, while Jasprit Bumrah was tidy with 1/31.