Joe Ironside, who grew up idolising Alan Shearer, scored the only goal as Cambridge stunned the newly-rich Magpies at St. James’ Park in one of the stories of the previous round.
This is now Cambridge’s first appearance in round four for seven years, while they have not reached the fifth round since 2000.
Mark Bonner’s side are currently 13th in League One and have little chance of getting promoted or relegated, so have even more motivation to keep their cup run going.
The Yellows are winless in three games, but a 2-0 loss to Bolton Wanderers on Tuesday evening was only their second defeat in their last nine matches in all competitions.
Meanwhile, Cambridge have won three games in a row on home turf and have only lost twice at the Abbey Stadium since the end of September.
Luton achieved the joint-biggest victory in this year’s FA Cup third round as they comfortably won 4-0 against League Two side Harrogate Town.
The Hatters, who reached the final of the competition in 1959, have not made it past the fourth round since 2013 when were in non-league and stunned Premier League outfit Norwich City.
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The club have climbed up the divisions since then and currently sit ninth in the Championship, only three points behind the playoffs.
Nathan Jones’s side have lost just one of their last nine games – winning six – and have won three of their last four away matches.
Luton are unbeaten in their previous seven meetings with Cambridge since the Yellows knocked them out of the FA Cup in 2015