Paul Cook's men head to the Kassam Stadium boasting a four-point lead at the top of the table and six wins from seven games. However, they can expect a stiff challenge against an Oxford side who have also yet to lose.
Chesterfield's success to date has been built on a solid defence that has shipped just three goals, the second-best tally in the Football League behind Championship leaders QPR.
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No League Two team has found the net more often than Oxford, though, meaning something has to give.
Third-place Fleetwood Town, who are level on points with Oxford, will be seeking a fourth successive win in all competitions when they visit Portsmouth.
Perhaps unsurprisingly given their respective histories, the two sides have never previously met.
The four teams currently occupying the play-off places all have home games on Saturday.
Exeter City and AFC Wimbledon will seek to maintain perfect records in front of their own fans against Newport County and Burton Albion respectively.
Wycombe Wanderers host struggling York City, who have yet to pick up a point on the road, while Morecambe welcome Dagenham and Redbridge to the Globe Arena.
Accrington Stanley scored their first goal in seven matches at Hartlepool United last time out, but have still mustered only one point all season and will be desperate to get a win on the board against near neighbours Rochdale.
If Hartlepool are to record back-to-back wins they must break their away goal-scoring duck at Bristol Rovers. Northampton Town, another team who have not found the net on their travels, take on Mansfield Town at Field Mill.
Elsewhere, Scunthorpe United play Plymouth Argyle, Bury face Southend United and Torquay United do battle with Cheltenham Town.