Pulisic netted an impressive opener, and then set up Jozy Altidore for a second.
Since 1990, the US men's national team has qualified for the World Cup, the quadrennial soccer spectacle, seven successive times, making it one of only seven countries in the world to do so.
18 - With two goals against Panama striker Jozy Altidore equalled Clint Dempsey's all-time USA World Cup qualifying tally of 18.
"On a night where so much was on line, maybe everything, we played in a way from the get-go that gave no doubt as to who was going to win the game", USA captain Michael Bradley said.
"[The crowd] came out on a big night for us", Altidore said.
Both sides had great scoring chances in the opening six minutes. It would be the ideal time to do it-and seal a berth in World Cup 2018 on a high note.
It was a banner night for the Americans, who jumped out to an early lead in front of the sold-out crowd of 25,303.
Pulisic got the opener after eight minutes when he sprinted free of the defence and slotted the ball home from a tight angle after rounding the goalkeeper.
Pulisic "is a star", said right back DeAndre Yedlin.
"We faced a team that was immensely better than us". It shows a lot about his qualities as a player, and what he's doing is fantastic.
Sure the USA finished first in the hex for the last three World Cups, but for the 2002 World Cup, where they nearly made the Final Four, they finished third in the hex.
Cameron played a full match for Stoke in Saturday's 2-1 win over Southampton, his first action since injuring a hamstring against Manchester United on September 9. Pulisic broke free and fed Altidore, who split the center backs and redirected the ball in from 5 yards for his first goal of the hexagonal - the 11th of 14 US goals in the hex that Pulisic played a part in.
Altidore then made it 3-0 just before the half, chipping in a penalty kick for his 41st worldwide goal.
'It's a big occasion, ' Arena said.
Christian Pulisic, the star American midfielder who just turned 19, has been repeatedly fouled by opponents, and the US will be seeking more offensive outlets. That left plenty of space for Panama to attack and in the seventh minute old-timer Blas Perez flicked on a pass to Gabriel Torres, who nutmegged Omar Gonzalez and had an open shot at goal, only to skew it well wide. While El Tri dominated the contest, it was T&T who took the lead midway through the second half through Mexico-based winger Shahdon Winchester. This was Panama, after all, in Florida on a hot night in October. After taking a handful of heavy knocks in the first 10 minutes of the second half, Bruce Arena took the youngster out for defensive midfielder Dax McCarty in the 56th minute to protect Pulisic from taking any more of a beating than he had to.
"This team is very dedicated", winger Hirving Lozano said. "Not just the three points, but the performance and the goal difference. Whenever you're in that situation I think it's a positive", Arena added.
"On a team note, it was great". It is becoming repetitive and exhausted to pile on the praise on Pulisic but we can not avoid the 800-pound gorilla in this U.S. World Cup qualifying - the ticket to Russian Federation is never booked without Pulisic's contribution.
And if they have learned anything on their long qualifying road - one that began with two humbling losses and the firing of their last coach, Jurgen Klinsmann - it is that nothing is certain, and that even a country accustomed to a quadrennial World Cup trip has to earn its place on the field before it can pack its bags.