Manchester United will once again look to the cups for consolation when they host Swansea City, while Chelsea, Liverpool and Manchester City will all be seeking to avoid embarrassment at the hands of lower-league teams.
It is now nine years since Arsenal beat United on penalties in the 2005 FA Cup final to claim their last piece of silverware, but as Premier League leaders their star is in the ascendant once again.
However, in old foes Spurs they face a side bolstered by the arrival of new manager Tim Sherwood and bubbling with renewed self-belief after a 2-1 success at United on New Year's Day.
Frozen out under former manager Andre Villas-Boas, Emmanuel Adebayor continued his impressive recent form with the opening goal at Old Trafford and team-mate Danny Rose has backed him to shine against his former club Arsenal on Saturday.
"He has been like a new signing," said the Spurs left-back. "He has scored four goals in his last five games, which is brilliant for us. Considering he didn't play a game from pre-season until a few weeks ago, his energy levels have actually been brilliant."
Arsenal's 2-0 win over Cardiff City on Wednesday was tempered by an ankle injury to goal-scorer Nicklas Bendtner, but French striker Olivier Giroud could be fit to face Spurs after an ankle problem of his own.
The two sides last met in the FA Cup in April 2001, when a Robert Pires tap-in earned Arsenal a 2-1 semi-final victory at Old Trafford.
United welcome Swans
United's loss to Spurs on Wednesday was their sixth of the Premier League campaign and left them 11 points off the pace, but they have shown impressive form in the cup competitions this season.
David Moyes's side have reached the UEFA Champions League last 16 and the semi-finals of the League Cup, and the FA Cup, which United last won in 2004, represents another means of salvaging their season.
Centre-back Jonny Evans says that the players are only slowly coming to terms with the impact of former manager Alex Ferguson's retirement in May.
"As a player I probably didn't realise the magnitude of it until I stepped back and looked at it from the outside," said Evans.
"Some of the results have not gone as planned, but to be fair to the manager and coaching staff, they have never been down in the dumps.
"They have always tried to improve us and I definitely think they are improving us in certain aspects of the game where maybe we were lacking."
The third-round draw yielded few opportunities for genuine upsets, but Liverpool, Aston Villa and Sunderland all face third-tier opposition in the shape of, respectively, Oldham Athletic, Sheffield United and Carlisle United.
Chelsea, meanwhile, visit Derby County, who recently won seven games in a row in the second-tier Championship under former England manager Steve McClaren, while Manchester City travel to Blackburn Rovers.
The biggest mismatch sees non-league Macclesfield Town host Championship side Sheffield Wednesday, who sit 63 places above them in the English league system, while Bolton Wanderers play Blackpool in a repeat of the 1953 final.