The defending champions needed two second half strikes to avoid a monumental upset after Guatemala skipper Carlos Ruiz had caught the Mexican defense napping to score in the fifth minute.
Substitute Aldo de Nigris put the Mexicans back on level terms when he scored after a goal-mouth scramble early in the second half before Manchester United forward Hernandez spared his team's blushes with a back-heeled winner in the 66th minute.
"This team is very strong at the core," Mexico coach Jose Manuel de la Torre, speaking through a translator, told a news conference.
"They know they can overcome any adversity. We knew that we could come back and we did." Hernandez scored a hat trick in Mexico's opening game against El Salvador and two more in their second pool game against Cuba and is the leading scorer in the tournament, with twice as many goals as his closest pursuer.
Mexico, missing five players who were suspended for failing a doping test earlier in the tournament, will now play Honduras in the semi-finals in Houston Wednesday.
"This is the situation we're in," de la Torre said.
"But the team is well prepared and adapting to the situation." The remaining two quarterfinals will take place in Washington DC Sunday with the United States playing Jamaica and Panama facing El Salvador.
The eventual winner of the tournament will represent North and Central America and the Caribbean at the 2013 Confederations Cup in Brazil.
Mexico, who have won the CONCACAF Gold Cup a record five times, were overwhelming favorites to get past Guatemala, ranked 125th in the world, 99 places below Mexico.
But they found themselves behind when Elias Enoc Valasquez launched a seemingly harmless clearance kick from inside his own half that Ruiz won the race to and flicked over the head of Mexico's advancing goalkeeper Alfredo Talavera.
Mexico dominated the rest of the first half, creating numerous opportunities but failing to find an equalizer, partly through poor finishing but also good defense from Guatemala.
Their persistence finally paid off when de Nigris scored at the second attempt after the ball rebounded off Guatemala goalkeeper Ricardo Jerez before Hernandez flicked the ball in off his right heel after a low cross from right winger Pablo Barrera.
Earlier, Honduras beat Costa Rica 4-2 on penalties on Saturday to reach the semifinals.
The match, played as the first leg of a double-header at the New Meadowlands Stadium, finished 1-1 after normal time and 30 minutes of extra time.
Honduras converted all four penalties they attempted but two Costa Rica players, Celso Borges and Alvaro Saborio, missed theirs, both blasting their spot-kicks against the crossbar.
Saborio also failed to convert a penalty in the second half of regular time when Honduras goalkeeper Noel Valladares, named man of the match, guessed correctly and dived to his right.
After a scoreless first half, Honduras opened the scoring in the 50th minute when striker Jerry Bengston tapped in his third goal of the tournament.
Javier Portillo broke free in the Costa Rica box and fired a low shot that goalkeeper Keylor Navas deflected to the unmarked Bengston.
Costa Rica equalized five minutes later when Dennis Marshall headed in a corner from Cristian Bolanos then won a disputed penalty when Marco Urena fell in the box after defender Victor Bernandez tugged his shirt.
Valladares was given a yellow card after protesting that Saborio had not placed the ball on the spot but regained his composure in time to pull off the save.
Both sides had chances to win the game in extra time but were unable to find the mark, resulting in the penalty shootout, which was sealed by Bengtson.
Honduras have now reached the semifinals in three of the last four editions of the tournament for North and Central America and Caribbean teams, while Costa Rica bow out on penalties for the second time in succession.
Honduras will play the winner of Saturday's second quarterfinal, between Guatemala and defending champions Mexico, in the semifinals in Houston.
The remaining two quarterfinals will take place in Washington DC on Sunday with the United States playing Jamaica and Panama facing El Salvador.
The eventual winner of the tournament will represent CONCACAF at the 2013 Confederations Cup in Brazil.
