Scientific research might suffer if Scotland splits from the UK and its links to research councils and UK research institutions are disrupted, George Osborne said.
He issued his warning following a lecture to the Royal Society in London, in which he called for a national debate on where the UK can lead the world in scientific excellence.
"One of the challenges that the SNP has, now that they've said to the people of Scotland, 'do you want to be independent?', is to explain how that will benefit the people of Scotland.
"I think one area where Scotland might suffer is scientific research. Scotland has fantastic universities and research facilities. It has been a centre for scientific inquiry since at least the 18th century, and I quoted from David Hume in my lecture.
"But it also benefits from being part of a network of research councils and research across the UK.
"That obviously would be disrupted if Scotland was independent and couldn't carry on in the way that it does at the moment.
"So I think the SNP has to explain how, actually, its science and scientific inquiry and all the jobs and the prosperity that brings would not be quite severely damaged by Scottish independence."
SNP MSP Dr Aileen McLeod said: "Far from an independent Scotland damaging research, it is having the powers to set our own policies that will allow us to protect our cutting-edge research sector."