They become the fourth side to win at Victoria Park already this campaign, Ryan Williams, Deane Smalley and Asa Hall all on target, but they had to work hard for their triumph.
Just five minutes had gone when Williams made the most of Pools' inability to clear their defensive lines and the U's midfielder, on loan from Fulham, neatly curled his low shot home from 16 yards.
Oxford were far superior in the first half, but Hartlepool levelled two minutes after the restart as Luke James was on hand in the area to slot in from close range.
However, the hosts did not make the most of their improved performance and were caught on the counter-attack.
Smalley was teed up in the area on 67 minutes and he picked his spot, firing low and finding the bottom corner.
James saw a close-range effort kept out by the legs of goalkeeper Ryan Clarke, but the visitors made sure of the points in stoppage time.
Pools goalkeeper Scott Flinders tripped Scott Davies in the area, allowing Hall to put away the penalty.
Colin Cooper's side were reduced to 10 men moments later when Steve Howard was red carded for a foul on Jonny Mullins.