Carlos Costly scored twice, in the 17th and 78th minutes, and Carlos Pavon scored in the 43rd for Honduras, while Nery Castillo converted a penalty in the 81st minute for Mexico, who suffered their second defeat in three matches in the final phase of qualifying in the region.
Honduras notched their first victory in three matches, taking their points total to four and breathing life into their qualifying hopes after losing to Costa Rica and drawing at Trinidad and Tobago on Saturday.
Mexico remained on three points thanks to their victory over Costa Rica at the Azteca Stadium on Saturday. They had lost to USA in their opening match in February.
Three teams from the six-nation final phase of qualifying advance directly to South Africa 2010, with the fourth-placed team playing off for a berth against the fifth-placed team from South America.