Grimsby boss David Artell is also hoping to secure his maiden victory after seeing his side play out a draw with MK Dons in his first game in charge.
Match preview
After Liam Manning decided to up sticks for Bristol City, the U's decided to turn to appoint Oxford-born Buckingham as his successor.
Despite taking over a side that had won four games on the bounce, Buckingham experienced a disappointing start to his tenure, as his side fell to a 2-0 defeat to relegation-threatened.
Although he was unable to claim his first win in midweek, the Oxford boss would have been content with a goalless draw against promotion rivals and league leaders Bolton Wanderers - a result that leaves the U's in third position and three points adrift of the top two.
While Oxford's promotion hopes will be Buckingham's main priority, he will now have the chance to take charge of his first FA Cup game after the U's beat Maidenhead United 2-0 in the first round in what proved to be Manning's final game in charge.
Having reached the third round in three of the last four seasons, the U's will certainly be confident about their chances of progressing from Saturday's cup tie.
Despite competing in the league below Oxford, fourth-tier Grimsby will still be dreaming of a place in the third round and a potential date with a Premier League side.
The Marines will have fond memories of last season's cup campaign, as they made their way to the quarter-finals for the first time since 1939, before their remarkable journey was brought to an end by Brighton & Hove Albion.
Grimsby are competing in the second round in back-to-back seasons after they eased to a 7-2 victory over Slough Town in a replay, making up for a disappointing 1-1 draw in the initial fixture.
Since recording that resounding victory, Grimsby have gone on to play three consecutive draws in League Two, and while they have made it six games without defeat, they would have been disappointed to give up leads in their last two outings against Sutton United and MK Dons.
After overseeing a 1-1 draw in Tuesday's away meeting with MK Dons, Artell will now turn his attention to his second game in charge, and he knows Grimsby will need to produce something special to beat Oxford, having failed to win any of their 13 competitive away games this season (D6, L7).
Oxford United FA Cup form:
W
Oxford United form (all competitions):
W
W
W
W
L
D
Grimsby Town FA Cup form:
D
W
Grimsby Town form (all competitions):
D
W
W
D
D
D
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Team News
The hosts will be without Greg Leigh and Sam Long, who are currently sidelined with calf and ankle injuries respectively.
Marcus Browne, who has been out of action since August, is progressing well in his recovery, but Saturday's contest may come too soon for the 25-year-old.
After serving a one-match suspension in midweek, Ruben Rodrigues is likely to return to the Oxford starting lineup.
As for the visitors, they are still unable to call upon the services of Charles Vernam, who is a long-term injury absentee.
Midfielder Evan Khouri and full-back Michee Efete are closing in on a return to action after recently returning to training.
Anthony Driscoll-Glennon was forced off in the first half of Tuesday's meeting with MK Dons, making him an obvious doubt for Saturday's cup tie.
Oxford United possible starting lineup:
Beadle; Stevens, Moore, Thorniley, Brown; McGuane, Brannagan; Mills, Rodrigues, Bodin; Harris
Grimsby Town possible starting lineup:
Cartwright, Mullarkey, Rodgers, Maher, Clifton; Hunt, Conteh; Pyke, Gnahoua, Khan; Rose