In their first competitive match since being eliminated at the group stage in Brazil, Vicente del Bosque's men made easy work of their Balkan visitors.
In Spain's first competitive game since its group-stage exit at the World Cup and the subsequent retirements of Xavi, Xabi Alonso and David Villa, Manchester City playmaker David Silva displayed his undoubted quality in an ultimately straightforward win.
Silva had a hand in four of Spain's five goals, winning a penalty that defender Sergio Ramos converted for the opener before playing a crucial part in Valencia striker Paco Alcacer's debut goal at the home of local rivals Levante.
Macedonia pulled one back through a Agim Ibraimi penalty but, although the Balkan outfit deserved a goal from a creditable performance, it was no match for the European champions.
Barcelona midfielder Sergio Busquets made it three on the stroke of halftime with Silva getting the goal his performance merited five minutes after the interval to end the game as a contest.
The gloss to a five-star performance came in the final minutes as Barca forward Pedro completed the rout by netting from another fine Silva pass.
Spain started well, but it was the visitor which surprisingly had the first real sight of goal as midfielder Ibraimi forced Iker Casillas into action, the Real Madrid goalkeeper tipping over from the Maribor man's free kick.
That scare seemed to jolt Spain into life, Cesc Fabregas curling narrowly wide of the far post following good build-up play from Vicente del Bosque's men.
And in the 15th minute the host did find a way through as Ramos executed a stylish chipped spot kick after Daniel Mojsov was ruled to have brought down Silva.
Silva was at the heart of most of Spain's forays forward and was involved again in its superb second, which arrived just two minutes later.
The 28-year-old curled an excellent ball to the far post for Juanfran to volley across goal and into the path of local boy Alcacer to fire into an empty net.
Many would have expected Macedonia to fold after going two behind but instead it rallied and got back into the game in the 28th minute through Ibraimi, who slotted into the bottom corner from 12 yards following Juanfran's poor challenge on Aleksandar Trajkovski.
But Macedonia continued to look fallible in defense and, after goalkeeper Tomislav Pacovski denied both Pedro and Silva, it conceded a third through Busquets' long-range strike, which deflected off Vanche Shikov on the way in.
Bosko Durovski's men almost made the dream start to the second half as striker Adis Jahovic was thwarted by a one-on-one save from Casillas.
Spain then punished Macedonia for Jahovic's profligacy, with Silva rewarded for an inventive display by finding the net with a low drive into the bottom corner.
Fabregas cannoned a shot off the crossbar before the hour mark, and Spain got its fifth in the first minute of injury time with a delightful lofted finish from Pedro to cap a win that extended an unbeaten run in qualifiers that stretches back to 2006.