The blue half of Manchester once again walked away happy after a 1-0 win.
Aided by Chris Smalling's sending off during a goalless opening period at the Etihad Stadium, Manuel Pellegrini's men took control after the interval as Sergio Aguero grabbed the decisive goal.
The Argentina striker's effort condemned United to a fourth successive league loss to its rival for the first time since 1970 and ensured Louis van Gaal was defeated in his maiden all-Manchester clash.
Anticipation was high as City attempted to end a three-game winless run in all competitions and the club's hopes were raised towards the end of a breathless first half, with Smalling given his marching orders after picking up two stupid yellow cards.
That, combined with center back partner Marcos Rojo being withdrawn through injury in the 56th minute, proved decisive as the home side took the points
City, already without star man David Silva, was dealt another blow when Aleksandar Kolarov limped off in the warmup, with Gael Clichy coming into the XI.
United had fullback issues of its own after Rafael da Silva picked up a knock in training to leave Antonio Valencia in an unfamiliar role.
Valencia was immediately tested, too, beaten by Aguero - who subsequently forced a first save from David de Gea.
But United responded quickly, Adnan Januzaj volleying just wide after being teed up by Robin van Persie's cushioned header.
The visiting side continued to look threatening, with the likes of Angel di Maria and Wayne Rooney - back from suspension - buzzing around in dangerous areas.
Yet the game then took on an end-to-end nature, with De Gea making world-class saves to deny Jesus Navas and Aguero in quick succession.
A decisive moment came in the 38th minute, however, when Smalling - who had already picked up a cheap yellow card for impeding Joe Hart as the City goalkeeper attempted to punt down field - flew into an ill-judged challenge on James Milner.
The first-half drama did not stop there, with City twice seeing loud penalty appeals turned down following challenges from Marouane Fellaini and Rojo.
City was unsurprisingly positive at the start of the second period, epitomized by Pablo Zabaleta finding himself in the United box to volley over.
Van Gaal's woes were added to as injury forced Rojo off, leaving United to field a makeshift back four featuring Valencia, Michael Carrick and youngster Paddy McNair.
Soon after being denied another penalty, Aguero gave City a 63rd-minute lead by coolly side-footing home Clichy's pull back after Yaya Toure had freed the left back.
Navas rattled the outside of the post, while at the other end Di Maria was denied by Hart after a stunning burst from Rooney.
Fellaini twice went close from set pieces and Toure missed two golden chances, curling wide and heading over.
But City, which remains third in the table, held on to claim the points and leave United just inside the top 10.