Pompey are considered one of the favourites for promotion and things looked promising for Guy Whittingham's relegated side when they took a 25th-minute lead through Patrick Agyemang in front of a league-record 18,000 strong crowd at Fratton Park.
Things got worse for Portsmouth just before the hour-mark when they lost Johnny Ertl to a red card and Oxford made the most of their numerical advantage to add salt to their opponents' wounds with further goals from Potter and Smalley.
While it was an opening day to forget for Pompey, promoted Newport enjoyed a fairytale start on their return to the Football League with a 4-1 home win over Accrington.
A brace from Chris Zebroski and goals from Harry Worley and Christian Jolley handed Justin Edinburgh's side the points in Newport's first game back in the top four divisions since 1988, with Danny Webber scoring a consolation for Stanley.
Mansfield, who were promoted alongside Newport, could not match the Welsh side as they lost 2-0 to Scunthorpe, for whom Matt Sparrow and debutant Sam Winnall were on the mark.
Fleetwood, who like Portsmouth are also fancied to go up, started their campaign with a 3-1 home win over Dagenham and Redbridge with debutants Mark Roberts, Jeff Hughes and Ryan Cresswell all on the mark for the victors. Rhys Murphy replied for Dagenham.
Another club tipped to do well, Cheltenham, were forced to settle for a point after Burton hit back from two goals down to earn a 2-2 draw at Whaddon Road.
Hosts Cheltenham took control with goals from debutant Jamie Cureton - who was stretched off after being clattered as he guided the ball into the net - and his replacement Byron Harrison but Burton recovered through efforts from Billy Kee and recent arrival Rory Delap.
Another player making his debut earned Exeter a 2-1 win over Bristol Rovers as Sam Parkin headed home a 79th-minute winner. Earlier, visiting forward Eliot Richards had cancelled out a goal from Exeter's former Rovers defender Danny Coles.
Chesterfield got their campaign up and running with a 2-0 win at Bury thanks to goals from Jay O'Shea and Marc Richards while Rochdale were 3-0 victors over Hartlepool, Matt Hogan, George Donnelly and Ian Henderson on the mark.
Barry Corr's early goal secured Southend a hard-fought 1-0 win against Plymouth and it was a similar story for Wycombe as a seventh-minute strike by debutant Paris Cowan-Hall earned them a 1-0 success over Morecambe.
York were 1-0 victors over 10-man Northampton, summer signing Ryan Jarvis netting with a last-minute header after Cobblers midfielder Darren Carter had been sent off for two yellow cards.
In Saturday's other game, a superb stoppage-time equaliser from centre-back Aaron Downes earned Torquay a 1-1 draw against AFC Wimbledon, who had taken an 87th-minute lead when Downes deflected Harry Pell's shot past his own goalkeeper.
- Sports & Recreation
- Patrick Agyemang
- Deane Smalley
- Alfie Potter
- Guy Whittingham