It is his dismissal for a challenge on Manchester City midfielder Alf-Inge Haaland in 2001 that most will remember, but his clash with Newcastle United centre-forward Alan Shearer later that same year may be a close second.
Champions United made the trip to Tyneside 13 years ago today on the back of a 4-1 victory over Everton, while the hosting Magpies were in buoyant mood in what was Sir Bobby Robson's 100th game in charge of the club, having won 4-1 away at Middlesbrough last time out, thanks in part to a brace from Shearer.
The two teams would go on to produce one of the Premier League's most memorable encounters, but it was Keane's actions and his subsequent comments that would equally live long in the memory.
French winger Laurent Robert fired the home side in front early on, but in the 29th minute United were level thanks to Ruud van Nistelrooy, who converted a downward header from former Newcastle striker Andy Cole.
The match's next two goals - scored in the 34th and 52nd minutes - went the way of the hosts. Firstly, Rob Lee's shot from distance got the better of Fabien Barthez in the visiting goal, before Greek centre-back Nikos Dabizas found himself with enough time inside the United area to fire his shot into the roof of the net.
However, within 12 minutes, the away side were level. Ryan Giggs reduced the arrears with a half-volley from Gary Neville's cross, while Juan Sebastian Veron struck his second goal for the club from the edge of the area.
Newcastle would not be denied, though, and with eight minutes remaining the winning goal came courtesy of Shearer as his low shot deflected into the net off United defender Wes Brown.
Yet, it would not be the end of Shearer's involvement in proceedings. In stoppage time, the striker prevented Keane from taking a quick throw-in, which resulted in the United captain throwing the ball at his opposite number's head, before slapping him round the face. Then, when the inevitable red card was dished out by referee Steve Bennett, Keane had to be dragged away from Shearer by his teammate David Beckham.
Speaking about the incident a year on, it didn't appear that Keane was full of remorse when he said: "I was sent off for pushing him, but if you're going to get sent off, you might as well punch him properly. It's the same punishment. You might as well get hung for a sheep as a lamb. It was just a push, though. Ridiculous."
NEWCASTLE: Given; Griffin, Elliott, O'Brien, Dabizas; Solano, Acuna, Lee (Barton), Robert; Shearer, Bellamy (Distin)
MAN UNITED: Barthez; G Neville, Blanc, Brown, P Neville; Beckham, Veron, Keane, Giggs; Cole (Scholes), Van Nistelrooy