Australia's hopes of progression and sealing a top-two berth will come down to their final group match against Paraguay on June 25 (June 26 AEST) after a nightmare afternoon at Seattle Stadium on Friday.
Popovic's call to bench Irankunda and Metcalfe, who scored in Australia's opening 2-0 win over Turkey, for Nishan Velupillay and Mathew Leckie, backfired as the US dominated.
Velupillay struggled and Leckie only had moments before hobbling off on the hour mark, while the co-hosts battered Australia on and off the ball.
But Popovic said his team had been overawed by the occasion, believing even if Irankunda and Metcalfe had played from the start it wouldn't have changed how the poor first half played out.
Even without superstar Christian Pulisic (calf), the US were on top in every element, bullying the Australians physically, dominating possession and explosive in attack.
"I'm not sure how much the personnel made a difference in that first half," Popovic said.
"It was warm for us out there, it was difficult, we found it difficult, and I think the players that came on would have probably struggled to last long in the first half.
"So we needed some fresh bodies for the second half to come on, we needed to stay in the game better than what we did in the first half, but you've got to give them (the US) credit as well."
Irankunda and Metcalfe added instant quality and attacking threats when they came on at halftime and World Cup debutant Cristian Volpato, who replaced Leckie, looked dangerous whenever he got on the ball.
"I would have preferred to start, of course," Irankunda said.
"For me, it was the biggest game. It was the game that I was most looking forward to. I would have loved to play from the start and create some things and score some goals.
"But, obviously, the coach decided different, he wanted to approach the game differently - which is fine with me, I play for the team, not for myself."
The US, even without Pulisic, battered Australia all day and took the lead in the 11th minute through a Cameron Burgess own goal.
Alex Freeman dealt the Socceroos a hammer blow by bundling home a header - that was initially ruled offside but cleared by VAR - to double the co-hosts' lead in the 43rd.
"I don't know if it was the occasion, but we looked sluggish, heavy-legged," Popovic lamented.
He later said his team failed to "match" the US.
"We found it difficult to win a challenge, to win a second ball," Popovic said.
"We were slow to every ball, and we couldn't really wrestle back any momentum, which made it difficult.
"And we conceded a couple of soft goals ... but we just looked flat and lethargic in the first half."
The healthy Australian contingent in the crowd of 66,925 fans were well and truly outnumbered by their deafening US counterparts, and the Socceroos looked intimidated and nervous.
Australia couldn't string passes together and were constantly under the pump.
"There wasn't much time on the ball, especially in the first half," midfielder Aiden O'Neill said.
Burgess's own goal headlined a nightmare game for the centre-back, who was uncharacteristically shaky on the ball and hooked at halftime.
Australia were far better after the break, with ther substitutes particularly lively, but it proved too little, too late.
"The reaction in the second half was outstanding," Popovic said.
Popovic lamented some of the refereeing calls but didn't want to use it as an excuse.
"I think today was, I wouldn't say the best day for the referee," he said.
"But overall we weren't good enough in the first half, second half we were."
The US (six points) lead Australia (three) in Group D, with Turkey and Paraguay facing off on Friday night.
"We know we've still got a good chance to get through," Popovic said.
"It's in our hands."
