Holders Spain top the section with 18 points from seven of 10 matches thanks to Saturday's 2-0 win over Slovakia, who also have 18 points but are second due to an inferior head-to-head record, while Macedonia are bottom on three points.
"We are going to freshen up the team," Del Bosque told a news conference previewing the match in Skopje.
"We haven't had much time to recover and it's better to give some of the players a rest," he added.
"We have some youngsters with a lot of vitality and we need to be fresh and active tomorrow.
"Anyone could play. If they are here it's because we think they should be and that means any of them would perform well."
With qualification looking almost certain, Del Bosque can afford to experiment and players who could get a run-out from the start include forward Paco Alcacer, midfielders Koke and Isco, defender Marc Bartra and goalkeeper David De Gea.
Deploying De Gea would be a vote of confidence for the Manchester United player, whose planned transfer to Real Madrid broke down in farcical circumstances last week when the paperwork was filed too late.
United coach Louis van Gaal has not used De Gea this season as the transfer saga dragged on, leaving his future with the English Premier League club uncertain.
Ukraine, who won 3-1 at home to Belarus on Saturday, are third in Group C on 15 points and assured of at least a playoff berth ahead of their match away to Slovakia on Tuesday.
The nine group winners and runners-up and best third-placed side qualify for the finals in France, while the eight remaining third-placed teams contest playoffs for the last four spots at the finals in France.
(Writing by Iain Rogers, editing by Martyn Herman)
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