Keane, the only survivor of a costly 1-1 qualifier draw in Skopje almost 12 years ago, became the first British or Irish player to complete a half-century of international goals when he went past England's Sir Bobby Charlton with an eighth-minute opener in Saturday's Euro 2012 Group B qualifier.
He doubled his tally for the evening after 37 minutes with a neat finish, and although there was a major scare for the Irish when Ivan Trickovski smashed a penalty against the crossbar three minutes later, Keane's contribution proved decisive.
Victory at the Philip II Stadium was imperative after earlier wins for Russia and Armenia, and the trio remain locked together at the top of Group B with 13 points each from six games.
Giovanni Trapattoni's side host the Slovakians at the Aviva Stadium in September and then head for Russia in matches which will have a major say in the destiny of the group.
Saturday night's win was all the more creditable as it was achieved without stalwarts Richard Dunne and Damien Duff, and with Keane nursing a groin injury which at one point left a question mark hanging over his participation.
Skopje had not been a happy hunting ground for Ireland in the past, with a 3-2 defeat in 1997 and the 1-1 draw in 1999 severely denting their qualification hopes for the 1998 World Cup and Euro 2000 respectively.
However, their luck changed markedly inside a dramatic opening 45 minutes as Macedonia's hopes of inflicting further misery on the men in green were comprehensively undone, and largely by their own failings.
Keane needed just eight minutes to complete a famous half-century when, after accepting Keith Andrews' pass, he was afforded both time and space to work his way into a shooting position.
His well-struck drive might have troubled goalkeeper Martin Bogatinov anyway, but the flick it took off defender Nikolce Noveski left the shot-stopper with no chance as the ball flew into the net to cue delirious celebrations on and off the pitch.
But Ireland goalkeeper Shay Given, who had earlier been targeted with a laser pen from the crowd, had to pull off a fine save from Goran Pandev at point-blank range with 13 minutes gone, and he was back on his feet in time to deal with Goran Popov's follow-up when it arrived at pace.
Simon Cox thought he had increased Ireland's lead two minutes later, only to have his strike harshly ruled out for offside and be booked for playing on after the whistle amid a cauldron of noise into the bargain.
The Republic's luck held when a stumbling John O'Shea brought Pandev down inside the box with the striker looking to have got beyond him, and German referee Florian Meyer waved play on.
There was an anxious, moment for Trapattoni when central defender Darren O'Dea landed awkwardly as he, Given and substitute Ferhan Hasani challenged for a high ball, but O'Dea's pain was eased markedly eight minutes before the break.
Central defender Boban Grncharov completely miskicked as he attempted to turn Noveski's pass back to his goalkeeper, and the ever-aware Keane raced in to slide a shot into the bottom corner.
The Macedonians were handed a golden opportunity to drag themselves back into the game when Meyer awarded a penalty for O'Shea's crude challenge on Pandev, but Trickovski let Ireland off the hook.
The atmosphere inside the stadium had changed markedly, and the chants of the small band of travelling fans were clearly audible, with their Macedonian counterparts having earlier voiced their displeasure at the break.
The home crowd's mood was not improved 11 minutes into the second half when Pandev's close-range strike was chalked off for handball as he controlled Popov's deep cross at the far post before stabbing a shot past Given.
The Ireland goalkeeper had to be at his best to turn away substitute Mario Durovski's curling 68th-minute effort as it arced towards his top corner, with the home side making a final desperate push.
But for all their possession, they were unable to unduly trouble Given who was well protected by the men in front of him to see the Republic across the finishing line with the minimum of fuss.