Jorge Sampaoli's side have lost all five of their encounters with la Roja, but will be buoyed by recent form which has seen them win five of their last six matches
The South American nation have met the reigning world and European champions five times previously, losing on every occasion.
Their most recent encounter also came in a friendly in Switzerland in September 2011, when Spain came from two goals down to win 3-2 in St Gallen thanks to an injury-time strike from Cesc Fabregas.
Vicente del Bosque's men also narrowly edged their last competitive meeting in the group stage of the 2010 World Cup, as goals from David Villa and Andres Iniesta were enough to seal a 2-1 success.
But despite their historical hoodoo against the Spaniards, Chile go into this latest clash full of confidence having won five of their last six matches.
Jorge Sampaoli's men sit in third place in the Conmebol qualifying section for next year's World Cup and are well placed to reach Brazil 2014 after beating Venezuela 3-0 on Saturday.
Juventus midfielder Arturo Vidal was among the scorers in Santiago and he, along with Barcelona forward Alexis Sanchez, will pose the most significant threat to Spain.
However, they will have their work cut out to compete with Del Bosque's all-conquering outfit - a team that is ranked number one in the world having lost just one of their last 29 games.
Spain go into the match primed to reach the World Cup after their 2-0 victory over Finland in qualifying on Friday, with their goals coming from Jordi Alba and Alvaro Negredo.
Their last game against South American opponents - last month's friendly in Ecuador - ended in a comfortable 2-0 success and they will be expected to record another victory as they prepare to round off their qualifying campaign with home games against Belarus and Georgia next month.
Goalkeeper Iker Casillas won his 150th cap during Spain's win in Helsinki but Del Bosque may use the Chile game to reward Barcelona's Victor Valdes for his superb early-season form with a start.
La Roja will have to make do without Isco, however, after the Real Madrid midfielder was forced to return home nursing an ankle injury.