The result in San Pedro Sula gives the U.S. men's national soccer team its first win after two consecutive draws at El Salvador and then Canada in Nashville, Tennessee, to open up the eight-team qualifying round for a spot at the 2022 World Cup in Qatar.
"Maybe we thought it was going to be easier than it was going down to El Salvador, Honduras. There are tough games, man. You see how hostile the crowds are, but the energy is amazing, the atmosphere is amazing,'' midfielder Tyler Adams said.
All three half-time additions -- Brenden Aaronson, Sebastian Lletget and Antonee Robinson -- scored goals, but the win will be best remembered for the incredible debut performance from 18-year-old striker Pepi.
Just two weeks after committing to play for the United States over Mexico, Pepi, 18, scored the winning goal and was involved in all three others.
The FC Dallas star was the standout player in his international debut, as he became the second-youngest USMNT player to appear in a World Cup qualifier, after only Pulisic.
"When I decided to play for the United States, I said that I would give all my heart to this team and I showed that tonight," Pepi said. "Gregg [USMNT coach Berhalter] told me I was going to start on the plane on the way here. It was very special, I was prepared for the moment and I took advantage of it."
Brayan Maya put Honduras ahead in the 27th minute of a one-sided first half as the Catrachos dominated before a horn-blowing full house at Estadio Olimpico Metropolitano.
Following the halftime break, Berhalter made several lineup changes, including introducing Robinson, whose 48th-minute shot off Pepi's initial attempt equalized the match.
In the 62nd minute, Pulisic was substituted off after he hurt his ankle. He needed treatment after a challenge then fell to the ground after trying to sprint on a dribble. He was replaced by Cristian Roldan.
"We'll get more information when he returns to London [for his club, Chelsea] on the severity of it," Berhalter said of Pulisic's injury.
Pepi then scored the U.S. squad's second goal in the 75th minute when he headed in DeAndre Yedlin's cross.
Aaronson effectively sealed the three points when he powered in a shot in the 86th minute, with Lletget then scoring in stoppage time, both set up by Pepi.
"We just fought,'' Lletget said. "We knew we just had to match their intensity. That was the biggest change in the second half.''
Aaronson also had scored the Americans' lone goal in the previous game, a 1-1 draw to Canada in Nashville.
"I was so fired up today, I don't know what kind of took over me, but I was just ready to go; and you could see it with all the subs. It was a spark,'' Aaronson said.
"I think it's really important that we did that just to show everyone that at times it's going to be a hard qualifying process, but we're ready for the challenges that'll come ahead,'' Robinson said. "We can respond to anything.''
The U.S. was without defender Sergino Dest and forward Giovanni Reyna because of injuries, and midfielder Weston McKennie was suspended a second straight game for violating the team's COVID-19 protocols.
Mexico leads the eight-team table with seven points, followed by Panama, Canada and the U.S. with five each. Honduras and El Salvador have two points each, Costa Rica has one point and Jamaica none. The top three sides will qualify for the World Cup in 2022, while the fourth-placed team will enter a playoff for a spot in Qatar.
The next three-match qualifying cycle begins for the U.S. on Oct. 7 in Austin, Texas, versus Jamaica. The U.S. will play at Panama on Oct. 10 and then will host Costa Rica in Columbus, Ohio, on Oct. 13.
The Associated Press contributed to this report.