The U.S. (5-2-1) moved into first place in the North and Central American and Caribbean finals with 16 points, one ahead of Costa Rica (4-1-3), which was held to a 1-1 tie at last-place Jamaica and also clinched.
"Obviously this is a huge, huge evening for all of us," U.S. coach Jurgen Klinsmann said. "It's a huge milestone whenever you make it to a World Cup."
The top three teams qualify, and the U.S. had to wait an hour after the final whistle to learn it was assured of a spot in the 32-nation field for Brazil next June. But when Honduras (3-3-2) held on for a 2-2 tie against Panama (1-2-5) in Tegucigalpa, the Americans had grabbed a berth with two games to spare.
"We're continuing the growth of the game here in the sport, we're improving, getting better and we've got to make sure we do well in Brazil to keep it going," Dempsey said.
Mexico (1-2-5) dropped into fifth on goal difference and seems likely at best headed to a playoff against Oceania champion New Zealand.
U.S. players, many carrying large American flags on sticks, celebrated their win with a lap around the field, saluting the crowd the whole way. Then they went to the locker room to wait out the Honduras game. About 1,000 fans stuck around to watch on the videoboard, chanting for Honduras.
Following wins over Mexico in qualifiers by identical 2-0 scores at Columbus Crew Stadium in 2001, 2005 and 2009, the U.S. Soccer Federation picked the same venue for this year's match. The capacity crowd of 24,584 taunted the Mexicans with chants of "Dos a cero!" and "You're not going to Brazil!"
Fans were so loud during "The Star-Spangled Banner" that anthem singer Kayleigh Schofield was forced to alter her tempo to match that of the crowd.
Johnson nearly scored off Donovan's cross in the third minute of the second half, but the pass was just ahead of him.
A minute later, the U.S. took just its second corner kick of the match. Jermaine Jones and Johnson both broke in from behind the penalty spot, and Mexico was slow to react as Johnson scored in 12th goal in 21 qualifying appearances. He was mobbed by teammates near the U.S. bench as fans set off a smoke bomb.
Donovan's goal, increasing his national team record to 57, set off a nonstop singalong for the closing minutes of the match.
"I'm proud of this team. I'm proud to be a part of it," Donovan said. "These guys put in a lot of hard work over the last two years and to have an opportunity in front of a crowd like this to qualify is pretty special."
O Eddie Johnson and Landon Donovan score goals in the second half to help the United States beat rival Mexico and earn a spot in the 2014 World Cup in Brazil.
• Thanks to a 2-2 tie between Honduras and Panama, the U.S. qualifies for the World Cup for the 7th straight time.
Note • Top three qualify, plus fourth-place team advances to playoff vs. Oceania winner
G W D L GF GA Pt
q-USA 8 5 1 2 10 6 16
Costa Rica 8 4 3 1 11 5 15
Honduras 8 3 2 3 10 10 11
Mexico 8 1 5 2 4 6 8
Panama 8 1 5 2 7 9 8
Jamaica 7 0 4 4 3 9 4
q-qualified for World Cup
Costa Rica 3, United States 1
Honduras 2, Mexico 1
Panama 0, Jamaica 0
United States 2, Mexico 0
Jamaica 1, Costa Rica 1
Honduras 2, Panama 2
Next U.S. match • Jamaica at Kansas City, Kan. Oct. 11 at 4:30 p.m.