Gareth Bale was a late injury scratch for Los Blancos, who had to come from behind but coasted thanks to a brace from Cristiano Ronaldo.
Angel Lafita gave the visiting team a shock lead after just a matter of minutes but Carlo Ancelotti's side was soon ahead with strikes from Pepe and Cristiano Ronaldo turning the game on its head before the break.
Isco put the win beyond any doubt midway through the second period before Ronaldo rounded off the victory with a sublime flick on Sami Khedira's cross.
However, the gloss was taken off the scoreline by concerns over the fitness of Gareth Bale, who missed out on what would have been his home league debut after suffering an injury in the warm up.
The pre-match headlines were dominated by the former Tottenham man, who was penciled in to start behind Karim Benzema in attack, but failed to make the starting XI after pulling up with what was believed to be a hamstring problem.
Isco retained his place in the side as a result, with Carlo Ancelotti making just three changes from the side that won 6-1 against Galatasaray in the UEFA Champions League in midweek.
Diego Lopez, Nacho and Asier Illarramendi all came in place of Iker Casillas, Sergio Ramos and Luka Modric.
The early stages were frantic as Ronaldo squandered two great chances following Isco’s low cross before Getafe took a shock fifth-minute lead.
Ronaldo lost possession to Miku in his own half and the Venezuelan laid the ball off to Lafita, whose effort from outside the area took a significant deflection off Pepe before flying past Lopez.
That stunned the home side into life and after a sustained spell of pressure, Madrid equalized.
Angel Di Maria floated a magnificent free kick towards the back post and after Miguel Angel Moya had denied the unmarked Ronaldo, Pepe knocked in the rebound from point-blank range.
It was no more than Real deserved, and Ronaldo made amends for his earlier error in the 34th minute as he converted from the penalty spot after Michel had handled the Portuguese’s initial free kick.
Getafe found its host particularly elusive in attack in the early part of the second half, yet the wasteful Benzema could not capitalize as he shot straight at Moya from a central position.
Moya was helpless in the 59th minute, however. Ronaldo took a quick free kick on the left flank, allowing Isco to burst across the penalty area and curl an unstoppable effort home for his fourth league goal of the season.
Ancelotti’s side was not content with three goals, though, and continued to bombard the Getafe goal.
Initially that was without reward as Moya denied Ronaldo before Alexis Ruano deflected an Isco effort wide.
The much-maligned Benzema then missed two more chances in the final 20 minutes as he headed crosses from Isco and Daniel Carvajal off target, while Ronaldo struck the post before Getafe's defeat was compounded four minutes from time as last-man Michel was shown a red card for a foul on substitute Jese Rodriguez.
That seemed to be that but things got even worse when Real added a fourth in stoppage time, as Ronaldo produced a clever back-heeled finish from Sami Khedira's right-wing cross to continue Real's unbeaten start to the season.