It was the U's first win in seven league games and gives their play-off prospects a lift, while damaging the top-seven aspirations of their visitors.
Lewis has had 12 games in temporary charge since Chris Wilder left the club at the end of January and chairman Ian Lenagan announced just before kick-off that a new manager will be appointed over the weekend.
Hartlepool had Simon Walton sent off for a second yellow card in the 75th minute following a foul on Sean Rigg. And just three minutes later David Connolly headed in the winning goal from David Hunt's free-kick.
There was nothing between the sides in the first half.
U's top scorer James Constable mis-kicked in front of goal and Connolly saw a shot turned around his near post by goalkeeper Scott Finders.
Jack Barmby went close for Pool in first-half stoppage time with a left-foot shot that U's keeper Ryan Clarke turned away for a corner.
Oxford had strong appeals for a penalty turned down after Rigg appeared to be brought down by Sam Collins.
Constable and Alfie Potter both squandered great chances to extend the lead late on.