"Every election this fall will be a referendum on this bill" if Congress passes reform, he said on ABC's "This Week."
McConnell said Americans have closely followed the healthcare debate and fear cuts to Medicare, tax increases and higher insurance costs.
If Democrats pass healthcare reform, McConnell said: "They can say, 'Ah, we got it done after 60 years.' And then they have to defend it from now until November. And I think it will be very tough to defend a lot of the things inside that bill."
He said the benefits of reform wouldn't kick in for four years but before then "massive cuts" would be made to Medicare.
"The tax increases kick in immediately," McConnell said. "So there's nothing -- just looking at the politics of it -- there's nothing but pain here for the next four years. Why in the world would (Democrats) conclude that that would be popular?"
But Health and Human Services Secretary Kathleen Sebelius, also appearing on the program, asserted Americans are "desperate" for healthcare reform even though polls show support has eroded significantly.
She said President Barack Obama would like to have Republican votes but he and GOP lawmakers had fundamental disagreements.
"The Republicans feel strongly that insurance companies should have less regulation than they do now, less consumer protection, less oversight," she said. "The president feels strongly that we need to change the rules of the road, that we can no longer have a private health system where insurance companies get to pick and choose, where they can lock people out and price people out. And that's really one of the fundamental divides."