Nine games remain for Juergen Klinsmann's US team as they bid for a spot in Brazil 2014 but with their next away game a tough trip to Mexico City, the loss puts pressure on the Americans.
In hot and humid conditions, the US struggled to find any sort of tempo but they grabbed the lead in the 35th minute thanks to some inspired individual play.
Midfielder Jermaine Jones lofted the ball gently over the home defence with a perfectly weighted pass to Clint Dempsey and the Tottenham striker finished superbly with a well-timed volley.
But the lead lasted just four minutes with Honduras midfielder Juan Carlos Garcia equalising with a brilliant overhead kick from inside the penalty area.
Honduras dominated the second half with strike pairing Jerry Bengtson and Carlo Costly causing plenty of problems for a shaky looking new US central defensive duo of Geoff Cameron and Omar Gonzalez.
Costly had an effort ruled out for offside and then headed just wide while Oscar Boniek Garcia flashed a drive just wide of Tim Howard's right hand post.
It was no real surprise then, when Honduras grabbed the winner with 12 minutes of normal time remaining - Bengtson, who plays in the US for New England Revolution, took advantage of some woeful defending and slotted into an empty net.
Few would argue with the outcome as Honduras had a better shape and looked more comfortable on the ball while the US struggled physically in the heat and lacked width in midfield and solidity at the back.
Olympic champions Mexico made a stuttering start to their bid for a 15th World Cup finals appearance when they were held to a goalless draw by Jamaica at the Azteca Stadium.
Costa Rica battled from two goals down to draw in Panama in the day's other match.
The battle for the region's three automatic spots in Brazil is already shaping as a fascinating one.
Jamaica produced a superbly disciplined and organised team effort to contain Mexico and scare them on the break, and the Reggae Boyz could well have headed home with all three points.
Reading midfielder Jobi McAnuff should have scored for the visitors in the eighth minute after his initial shot struck the post and he scuffed the rebound into the welcoming arms of Mexico keeper Jose Corona.
Corona was in action again when he tipped a Rodolph Austin effort wide as Jamaica created the chances despite Mexico enjoying the lion's share of possession.
After the break, Jamaica forward Ryan Johnson shot timidly at Corona after breaking through on goal and then it was the turn of Reggae Boyz keeper Donovan Ricketts to spring into action as he twice foiled Manchester United striker Javier Hernandez from close range.
The Mexican crowd turned on their team - booing every touch while cheering on Theodore Whitmore's Jamaicans, who will take great heart from their point.
The US return to action against Costa Rica in Denver on March 22 and with a road trip to face Mexico in Mexico City four days later they will be desperate for a win.
Six teams are battling for three automatic qualification spots from CONCACAF for the finals with the fourth-placed team playing off with the champion of the Oceania region.