The sides, both of whom have been in the Conference in recent years, occupy the two relegation spots in the division with just two points from six winless fixtures.
Exeter - boosted this week by the signing of former captain David Noble from Oldham Athletic - have lost their last two matches on the bounce, while Oxford have shown signs of turning their form around with draws against Dagenham and Redbridge and Southend United.
And Exeter manager Paul Tisdale believes the plight of the clubs gives the meeting between the two an extra edge.
"The fact that we haven't won a game this year yet and the fact that we're playing a team that hasn't won a game either makes it feel that more important," he told the club's official website. "It's a very big game and three points that we both desperately need and want.
"We're certainly not going to give it anything less than our best."
Carlisle United are the only other team who remain winless in League Two this term and they meet a Bury outfit who have not been defeated since the opening day of the campaign.
Five wins from six matches have seen Burton Albion climb to the top of the division and manager Gary Rowett, who turned down the chance to talk to Championship club Blackpool this week, welcomes York City to the Pirelli Stadium on Saturday.
York's remarkable run of five consecutive draws came to an end with a win against Stevenage last time out, while Burton have conceded just three goals so far this season.
Cheltenham Town - Burton's closest challengers at the top of the division - visit Luton Town, who are winless in five.
Morecambe's failure to pick up a victory from their last two fixtures has seen them slip from first to third, and they could be overtaken by opponents Plymouth Argyle on Saturday.
Shrewsbury Town will be looking to climb into the top three when they visit Stevenage, while surprise package Wycombe Wanderers can continue their impressive start at home to Mansfield Town.
Accrington Stanley, who parted company with manager James Beattie on Friday, host AFC Wimbledon as they bid to build on their first win of the season, and Northampton Town could strengthen their position in the top seven at Newport County.
Elsewhere, Hartlepool United welcome Tranmere Rovers to Victoria Park, Southend face Portsmouth, and Dagenham are at home against Richard Money's Cambridge United.
