Santa Cruz out of Paraguay qualifiers
The Blackburn Rovers striker is suffering from tendonitis in his left knee, a team spokesman said on Friday.
The South American group leaders, on course for a fourth successive World Cup appearance, will also be without injured left back Claudio Morel Rodriguez for the two games.
Paraguay have 23 points from 10 games, six ahead of second-placed Brazil.
They visit Uruguay on March 28 and face Ecuador at high altitude in Quito four days later.