The 54-year-old was appointed as the USMNT manager for the summer’s World Cup, in which he took them to the last 16 before being knocked out by Belgium.
He leaves to take over from Michael Carrick at Manchester United as the only manager not to win a trophy with the USMNT.
Pochettino will officially take the reins at Old Trafford on November 19, following the USA’s two games against Haiti.
The former Tottenham and Chelsea boss has been linked with a move to Man United for years and famously had a private lunch with Sir Alex Ferguson back in 2016.
Speaking to reporters ahead of the USMNT’s game on Saturday (November 13), Pochettino was in tears.
“Normally it's the opposite. You're sacked and you cry because you want to stay. For this case it's the opposite. It's a really tough decision, but at the same time I'm excited for that step,” he said.
“The staff and the players, I want to say thank you so much for the last two years. You made me feel really happy sharing an amazing project. It's difficult now for me to finish.
“We were very excited to share a project which we really believe in and are evolving together, it makes the decision harder," he explained as he continued to wipe away tears.
“It's a sad decision but we are professionals, and we need to try to find the next step to make your dreams come true. We increased the federation and around the world too.
“I didn't prepare a speech; I am talking from the heart. We recovered our motivation and the capacity to dig deep.
“I want to recognise the value from us and me. Big thank you. You respect your work. You never lie to us. That is a difficult decision but we need to move forward.”
Pochettino’s first game as Man United boss with be against Liverpool at Anfield on November 22nd.