The match in Skopje featured first against last in the section and heavyweights Spain effortlessly controlled proceedings despite fielding a weakened team.
Juan Mata was the architect of the only goal in the eighth minute when his hopeful cross from the right evaded flapping Macedonia goalkeeper Tome Pacovski, cannoned off the far post on to his head and into the net.
With eight of 10 matches played, Spain lead on 21 points, two ahead of Slovakia after they were held to a 0-0 draw at home by Ukraine, who are a further three points behind in third.
The nine group winners and runners-up and best third-placed side qualify directly for the finals in France, while the eight remaining third-placed teams contest playoffs for the last four spots.
Chasing a third straight continental triumph, Spain can make sure of their place with a home win over Luxembourg on Oct. 9 before they play in Ukraine three days later.
“They were aggressive and put a lot of intensity into the game,” Mata told Spanish television.
“We did our homework and we have classification within our grasp now,” added the Manchester United midfielder.
Spain coach Vicente del Bosque made six changes from the team that started Saturday’s 2-0 win at home to Slovakia.
Isco and Santi Cazorla came into the midfield for Andres Iniesta and Cesc Fabregas, Mata replaced Pedro up front and David De Gea was deployed in goal instead of captain Iker Casillas.
After grabbing the early lead, Spain launched waves of attacks without creating any clear chances before fullback Dani Carvajal almost scored an identical second.
He floated the ball in from the right and it sailed over Pacovski and ricocheted away off the frame of the goal.
Macedonia looked slightly more threatening at the start of the second half and winger Ferhan Hasani clipped a free kick just over the crossbar three minutes after the break before Spain reasserted control.
They have kept clean sheets in their last six qualifiers and their surprise 2-1 defeat to Slovakia in Zilina in October is their only reverse in their last 21 qualifiers away from home since a 2-0 defeat to Sweden in October 2006.
(Writing by Iain Rogers, editing by Toby Davis)