Argentine Pochettino, the former Tottenham, Paris Saint Germain and Chelsea coach, was brought in last month to take over a team which had won just once in their last seven games.
He will lead the USA into the 2026 World Cup, which they are co-hosting with Canada and Mexico, and while he had only five days to work with his new squad his influence was already evident.
The USA set up in a flexible 4-2-3-1 formation and it was clear from the outset that Aidan Morris had been trusted with the key role as the anchor in the midfield.
Middlesbrough midfielder Morris was not part of the team which was eliminated in the group stage of Copa America in July, but the 22-year-old more than justified Pochettino's faith in him with a confident and industrious display.
The Americans were moving the ball around with confidence and energy in the opening stages but, as so often under previous head coach Gregg Berhalter, were unable to create clear openings in the final third.
Panama, who beat the USA in Copa America, were content to let Pochettino's new-look side keep possession and they also offered occasional reminders of their speed and potency in attack.
Re-called USA keeper Matt Turner dealt comfortably though with Edgar Barcenas's shot from distance in the 26th minute but Eduardo Guerrero went closer with a drive into the side-netting.
The first real opening for the USA came six minutes before the break when Christian Pulisic sent Brenden Aaronson clear but his low shot was pushed away by keeper Orlando Mosquera.
Then on the stroke of half-time, Josh Sargent had a wonderful chance to open the scoring from close-range but he leaned back and put his left-foot effort harmlessly over the bar.
But after the interval, the Texan crowd didn't have long to wait for the first goal of the Pochettino era.
Four minutes after the restart, after good work from Fulham's Antonee Robinson to keep the move alive down the left, Pulisic played a smart "one-two" with Aaronson and the winger got to the byline and his cross was smartly side-footed home by his Milan team-mate Musah.
Building something
It was Musah's first goal for his country in his 42nd appearance for the national team.
Panama reacted positively and Turner had to produce a double save to keep out a shot from Barcenas and Jose Rodriguez follow up effort.
The fluency of the USA performance was inevitably impacted by the usual friendly match slew of second-half substitutions and they were fortunate that Panama sub Jose Fajardo"s sliding effort at the back post flashed wide.
But in the final seconds of added time, the USA made sure of a winning start for their new coach when Haji Wright broke down the left and his low cross was slotted home by fellow sub Ricardo Pepi to make it 2-0.
"It's a very good feeling. It was a really, really tough game for us," said Pochettino.
"Little by little (we are) building something. The objective is 2026, but I think happy because we were solid and a very professional performance and we competed in a very good way. (But) it's only the first step to improve," he added.
