The US finish top of CONCACAF Group A on 13 points with Jamaica, who beat Antigua and Barbuda 4-1, also going through to the final six of qualifying while Guatemala missed out on goal difference.
Juergen Klinsmann's team suffered an early scare when Carlos Ruiz broke away and latched on to a long ball, finishing coolly to put Guatemala 1-0 up in the fifth minute.
But just five minutes later the US was back on level terms.
Dempsey headed on a corner at the near post and defender Carlos Bocanegra drove home his 14th career goal for the national team.
The Tottenham striker then put the US ahead in the 18th minute when he converted a low cross from the impressive Eddie Johnson.
Dempsey made it 3-1, nine minutes before the break, after a smart exchange with Michael Bradley, who was a dominant figure in the US midfield.
With Guatemala needing goals to get back in the frame for qualifying, the US kept things tight in the second half and could have even extended their advantage - Johnson missing a great chance to score when he mis-kicked inside the area.
The win, and progress to the final six, though was never in doubt after the first half and former Germany international Klinsmann was pleased with his team's display.
"The team stepped it up and we created the amount of chances we wanted to, I wished we could have had some goals in the second half too but I thought the performance was really, really good," he told ESPN. "The crowd was amazing and really helped the whole team...I think Guatemala never had (even) a little bit of a chance," he said.
The US face a friendly away to Russia before next year's final round of CONCACAF qualifying in which the top three out of the six nations will qualify for the 2014 World Cup finals in Brazil.
Canada's hopes of reaching the finals ended in abject humiliation after they were destroyed 8-1 by Honduras with the USA, Jamaica and Costa Rica progressing to the next round.
Six nations will compete next year for three automatic spots at the finals, with Mexico, who had already booked their place, also joined by Honduras and Panama after Tuesday's games.
Victory in Honduras would have secured a place in the final qualifying round for Stephen Hart's Canadian side but instead they headed home after one of the darkest night's in their history.
Canada, who last appeared at the World Cup finals in 1986, were 4-0 down by the 32nd minute and the final score was almost as bad as their 8-0 loss to Mexico in 1993.
Honduran strikers Jerry Bengston and Carlos Costly each claimed hat-tricks in the rout in San Pedro Sula.
"You are supposed to go down all guns blazing. We were horrible," Hart, whose job is now in doubt, said.
Panama left it late to secure the point they needed to be sure of a place among the last six teams with Nelson Barahona equalising in the 77th minute against Cuba.
Alberto Gomez put Cuba in front in the 38th minute with the team's only goal in their six third-round qualifying games.
Jamaica's 4-1 victory over Antigua and Barbuda in Kingston meant they moved ahead of Guatemala into second place and into the next round.
Two goals in the final 12 minutes from Jamaican winger Dane Richards made sure of progress by goal difference over Guatemala.
First half goals from Demar Phillips and Nyron Nosworthy had been met with a 61st minute response from Antigua and Barbuda's Quinton Griffith, which threatened the Reggae Boyz' chances of progress before Richards' double strike.
Mexico finished with the maximum 18 points in Group B, rounding their campaign off with a 2-0 win over El Salvador with second half goals from Oribe Peralta and Javier Hernandez.
Costa Rica made sure of second spot in the group with a 7-0 crushing of Guyana - Randall Brenes and Alvaro Saborio both scoring twice. Guyana had defender Walter Moore sent off in the 50th minute.