Pace spearhead R Vinay Kumar bagged six wickets to help Karnataka skittle out the 44-time winners for a paltry total at the M Chinnaswamy stadium.
Abhishek Nayar did not come into bat as he underwent medical treatment after suffering an injury during Karnataka's first innings.
At stumps, Karnataka were struggling at 10 for two in their second innings with a lead of 168 runs with eight wickets in hands.
When the stumps were drawn, night-watchman Abhimanyu Mithun was batting on 4 while Ravi Kumar Samarth was yet to open his account.
Uthappa and K L Rahul made four and two, respectively before they were picked by Mumbai's star bowler Shardul Thakur and Balwinder Singh Sandhu.
Opting to bat, Karnataka made 202 all out in their first innings with Robin Uthappa top-scoring with 68 runs and was ably supported by Manish Pandey (34), who stitched a crucial partnership of 81-run for the third wicket after the hosts were in trouble at 34 for two.
Mumbai batsmen were tormented by Karnataka bowlers, with six of their batsmen getting out without opening their account. Only two players - Iyer and Yadav - reached double digits of 15 and 12 runs respectively.
Kumar ran in hard and wreaked havoc by picking up back-to-back wickets on two occasions.
Kumar drew his first blood when he got opener Akhil Herwadkar trapped leg before for zero in the very second ball of Mumbai's innings and soon Mithun (1-23) trapped Shreyas Iyer for 15.
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