Summer signings Rob Duffy and Andy Burgess ensured Oxford enjoyed a winning return to non-League football following a 44-year absence.
Duffy slotted past Craig Mewson from the spot after being upended inside the box by the Halifax goalkeeper.
The visitors offered little in attack and were punished by Burgess' strike.
The former Rushden midfielder sealed the three points in spectacular fashion with a thunderous left-footed drive that found the top corner.