The Brazilian said his players were up to the challenge of the European champions, who will set a world record of 15 successive international victories if they win the Group A match in Bloemfontein.
South Africa need a point to make sure of progressing to the semi-finals of the two-week World Cup warm-up event or face the embarrassment of ceding their last-four place to Iraq.
"We need to play with personality. If we do this, I'm confident we will make it. I have 100 percent confidence my players with get us through," Santana told reporters on Friday after their final training session.
The coach scoffed at suggestions he might he forced out if next year's World Cup hosts South Africa, who drew with Iraq and then beat New Zealand in their first two group games, capitulated against the Spaniards.
"This tournament remains a vital preparation for us on the road to the World Cup," he said.
"We still have a year to prepare and a lot of good friendlies organised. This is part of that preparation."
Defender Matthew Booth agreed with a suggestion it was possibly the biggest game in the careers of many of the South African players.
"Without question, it is not often you play against the number one team in the world and especially coming up against a strike force of (Fernando) Torres and (David) Villa," he said.
"Their whole squad is full of experience and talent."
