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 has met the reigning world and European champion five times previously, losing on every occasion.
The most recent encounter also came in a friendly in Switzerland in Sept. 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.
Despite the historical hoodoo against the Spaniards, Chile goes into this latest clash full of confidence having won five of its 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, Chile will have its 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 its last 29 games.
Spain comes into the match primed to reach the World Cup after a 2-0 victory over Finland in qualifying on Friday, with the goals coming from Jordi Alba and Alvaro Negredo.
The team's last game against a South American opponent - last month's friendly in Ecuador - ended in a comfortable 2-0 success and Spain will be expected to record another victory as it prepares to round off its 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.