Obama, a Democrat, said the Republican candidate lacked a plan for storage of the waste. It was among several energy-strategy ideas that Obama said were "not serious energy policies."
Obama was speaking in Nevada, a state where proposals to build a nuclear waste disposal site at Yucca Mountain have generated strong opposition.
He also took aim at McCain's plan to allow more offshore U.S. oil drilling.
"It doesn't make sense for America," Obama said. "In fact, it makes about as much sense as his proposal to build 45 new nuclear reactors without a plan to store the waste some place other than right here at Yucca Mountain," the Illinois senator said.
The U.S. Energy Department has applied for a license to operate a long-delayed nuclear waste dump at Yucca Mountain, about 90 miles (145 km) from Las Vegas.
Opposition in the U.S. Congress to the Yucca Mountain waste site is among the hurdles it faces. Senate Majority Leader Harry Reid, a Democrat from Nevada, is among those who oppose it.McCain, an Arizona senator, backs the project, while Obama is against it.
Asked his views on nuclear power in Jacksonville, Florida on Friday, Obama said, "I think that nuclear power should be in the mix when it comes to energy." But he added, "I don't think it's our optimal energy source because we haven't figured out how to store the waste safely or recycle the waste."
Obama supports using federal research and development dollars to explore whether nuclear waste can be stored safely for reuse.