On average mice can normally run for only around 90 minutes and 900 metres before becoming exhausted.
But scientists found that giving the mice one of two experimental drugs, neither commercially available, could significantly increase their endurance.
Four years ago researchers bred genetically engineered mice that could run much further than normal, but this is the first test to prove that drugs can have the same effect.
One of the drugs lengthened the amount of time the mice could run by 44 per cent, allowing them to keep going for more than two hours.
"It's tricking the muscle into 'believing' it's been exercised daily," Dr Ronald Evans of the Salk Institute in California, who carried out the study, said.
"It's basically the couch potato experiment, and it proves you can have a pharmacologic equivalent to exercise."
The second drug had to be used in conjunction with exercise to have any effect, the research found, but improved the animal's running distance by 70 per cent and their endurance levels by 77 per cent after four weeks.
Both drugs, were able to affect parts of the muscles which usually only respond to exercise, the findings, published in the journal Cell, show.
But instead of building muscles, like steroids do, the drugs appeared to "reprogram" the slow-twitch fibres within the muscle, needed for endurance, allowing them to work for longer without feeling tired.
Scientists believe that both drugs, neither of which are available commercially, could be used to treat muscle wasting conditions, such as muscular dystrophy.
"It is highly likely that these drugs could have similar effects in humans.
But, it is important to note that at this point these drugs are not approved for human use," Dr Vihang Narkar, one of the other scientists involved in the study said.
The scientists added that they were aware of the potential for the drugs to be used to boost athletes' performance and have developed a test capable of detecting the presence of both in blood and urine.
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