The former Norwich boss had been under mounting pressure to quit following Northern Ireland's poor performance in the qualifiers. Defeat to Estonia on Friday ended their hopes of participating in the tournament.
"I have had four and a half fantastic years working with the Irish Football Association and a lot of hard work has been put in by many people over this time to help improve Northern Ireland football," said Worthington in a statement.
"I feel it is only right to give the Association and players the opportunity and time to move forward and that is why I have decided that Tuesday night's game will be my last in charge.
"I understand their frustration over the last three games; but when you look at the incident in the Serbia game and the game away to Estonia, and then the game at home against Estonia, this is the fine line in football."
Worthington's final game in charge will be the qualifier with Italy tomorrow night.