Slovakia surprised the Spaniards 2-1 in Zilina in October and top the section with a maximum 18 points from six matches, with Del Bosque's side three points behind in second place ahead of the match in the northern city of Oviedo.
"This is a key moment in the classification process and all the players are very focused," Del Bosque told a news conference.
"We expect them to play with six players behind the ball," he added. "We have to have sufficient patience, we are preparing for that and hopefully it will come off well for us."
Spain have not lost at home in qualifying for a major tournament in 30 matches spanning more than a decade, their last reverse coming against Greece in June 2003.
Whatever Saturday's result, both sides look set to secure places at next year's tournament in France, when Spain will be chasing an unprecedented third consecutive continental triumph.
Ukraine are three points behind Spain in third place before Saturday's home game with Belarus, who are a distant fourth on four points.
The nine group winners and runners-up and best third-placed side qualify for the finals while the eight remaining third-placed teams contest playoffs for the final four berths.
Andres Iniesta, whose pace and skill should help find a way through the Slovakia defence, said Spain must also make sure they are tight in defence to avoid another upset defeat.
"These days any opponent can make things difficult for you," he told an earlier news conference.
"They close ranks very well, they cut off any route through and they mass a lot of people in the middle to make things uncomfortable for us," added the Barcelona playmaker.
"We have to be ourselves, move the ball quickly and rely on our forwards to throw them off balance."
After taking on Slovakia, Spain play fifth-placed Macedonia in their next qualifier in Skopje on Tuesday.
(Writing by Iain Rogers, editing by Ken Ferris)
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