A 2-1 defeat at home to Burton Albion on Saturday extended a poor run for the U’s, who have collected a single point from the last four Sky Bet League Two games.
It has seen them slip to sixth place, six points adrift of the top three.
Lewis acknowledged at the weekend there were senior players struggling for form and the side is likely to be shaken up tonight.
He said: “We’ve got an opportunity to freshen it up.
“We have one or two people not in form, so they might have to come out of the side – that’s the way it is.
“No-one is not giving it a go, it’s just sometimes it’s good to have a little rest.
“We are getting people back and there’s room to do it.”
One change will be enforced, with Dave Kitson out for at least a fortnight with a recurrence of the hamstring injury sustained last month.
David Connolly, who impress-ed as a substitute against the Brewers, is likely to take his place.
Elsewhere, United could look to Josh Ruffels, who has not featured in the last two games, for fresh legs to liven up the middle of the park.
There is also scope for change on the left flank, where Sean Rigg, if fitness permits, would provide more balance than the right-footed Deane Smalley.
The back four may not be altered, but after conceding nine goals in four games it is an area Lewis wants to see immediate improvement.
He said: “We’re normally good defensively, but in the last couple of games we’ve not been quite ‘at it’. We need to really focus on that and be solid.”
The clash marks Lewis’s tenth game in charge, but the last few results have led some to question whether he is the right man for the job.
Being in the spotlight does not faze Chris Wilder’s former assistant, who said: “I try not to think about it, really.
“I just try to think about what we think are the right decisions.
“You have to make loads every day, but I’m backed up by the staff, so I’m happy with it.”
A goalless draw at Portsmouth on Saturday lifted Cheltenham to 12th and with no injury concerns they are likely to be unchanged tonight.
Oxford Utd: from Clarke, Hunt, Mullins, Wright, Newey, Williams, Wroe, Rose, Smalley, Constable, Connolly, Potter, Marsh, Rigg, Ruffels, Davies, Raynes, Henly.
Cheltenham Tn: from S Brown, Ihiekwe, T Brown, Elliott, Jombati, Deering, Richards, McGlashan, Gornell, Vincent, Harrison, Cureton, Kotwica, Noble, Taylor, Brundle, Braham-Barrett, Roberts.