For decades, this sporting rivalry, borne as a result of neighbouring cities enjoying industrial booms in decades gone by, has been one of the standard-bearers of the English top flight.
Dramatic late goals, red cards, on-pitch brawls and managerial arguments—this fixture has seen it all, and the rivalry between the two sets of fans is one which is bettered by few others throughout the world.
Some supporters of these two clubs see the fixture as the biggest rivalry of the domestic season, while others place the local derby higher—Manchester City vs. United, Liverpool vs. Everton.
Perhaps so, but there is no denying the depth of feeling that goes into this particular matchup.
Here are four worldwide rivalries which can lay claim to being up there with United-Liverpool in terms of fan feeling, importance or coverage.
Liverpool and Manchester United meet on Sunday for the 160th league occasion, with the gap between the teams as big as it has been in the past three decades.
The Red Devils are intent on regaining the league title which was taken from them last season, while the Reds are in full rebuild mode.
Don't expect that to make the day any less fractious or tense though; Brendan Rodgers' team were far and away the better side in the first tie of the season at Anfield, but lost 2-1 after a controversial Jonjo Shelvey red card.
These encounters always have an element of fire about them and, too often, disturbing chanting between the two sets of supporters, the likes of which have no place in football.
The teams themselves have enough of a rivalry between them to make this one of the biggest in the world game.
Perhaps one other match in the entire British Isles can lay claim to being as big as the Liverpool vs. Manchester United fixture, but it's not one which is likely to be seen for some time.
Scotland's big two, Rangers and Celtic, have dominated the landscape of football north of the border for three decades, but now the Blue half of Glasgow reside in League Three amid financial ruin and face an arduous journey back to the top.
Meanwhile, the Hoops should sweep up the title with ease each year that passes, in the meantime.
When they meet again though for the first time, expect it to be a massive occasion.
This notoriously raucous derby match brings out the best in fanatical support—and sometimes the worst, with sectarian chanting an issue, amongst other problems.
Red cards are the rule rather than the exception in this game.
El Clásico is one of the game's most-viewed fixtures, with Real Madrid and Barcelona two of the biggest and best clubs on the planet competing at the top end for domestic and continental trophies alike most seasons.
Two fanatical groups of supporters, huge stadiums and some of the world's best (and best paid) players on show always make for an incredible occasion, with much of the country, even those who do not necessarily support one of the teams, divided into two.
Barcelona have pretty much sewn up this season's La Liga title already, but Real won last season—between them, they account for 53 championship victories.
The battle for supremacy is not merely restricted to the teams on the pitch, but ongoing spats in the boardroom and furious arguments in the stands.
There can be no argument that the fiercest rivalry in Europe—that is to say, in countries with European affiliation, at least—belongs in Turkey.
Fenerbahce and Galatasaray contest the so-called Intercontinental derby, given that the two teams occupy different parts of the same city (Istanbul)—Fener from the Asian side, Gala from the European.
The levels of support in this fixture transcend cultural or sporting differences into full-on violence, and not only on the odd occasion either.
This probably isn't a match you want to be at if you're sat amongst the losing supporters. Or if you have an aversion to flares being lit at close proximity.
River's relegation briefly caused an absence of the spectacle, but this is a match which regularly sees police officers put in a bit of overtime. The clash in October saw more than 2,000 combined police and security personnel in attendance—and still there was crowd trouble.
The two biggest clubs in Argentina and their fans understandably have a certain amount of pride to uphold, but matters in this match do go beyond the result too often.
Of course, holding up a giant inflatable pig donned in your rivals' colours is hardly the best way to calm down incendiary moments, is it?
This rivalry might just be the biggest in world football.