The former Northern Ireland boss had been in charge of the club since March 2013, when he took over from Gary Mills, and guided York to a seventh-placed finish last term.
However, following their 1-0 play-off semi-final defeat to Fleetwood Town, York have made a poor start to the current campaign and sit 22nd in England's fourth tier.
Worthington believes his departure gives the club, who have only picked up one league win this season, plenty of time to turn their fortunes around.
"After Saturday's result [a 3-1 defeat at Newport County] and in the best interests of York City, I have made the difficult decision to leave the club," he said.
"I feel the timing of my departure will give the players ample number of games to gain the points needed to ensure York City finishes in a good position in League Two by the end of the season.
"In recent weeks, performances have not been up to my high standards and I take full responsibility for this as manager.
"I would like to thank the board and the McGill family [York's owners] for their tremendous support during my time at the club.
"We have had a great working relationship and they have given me all the assistance I have needed. The supporters and the players should be very grateful to them for their loyalty, commitment and hard work.
"I have enjoyed a wonderful time at York City over the past 18 months. The fans have been fantastic throughout."
A statement from the York board of directors thanked Worthington for his efforts, adding: "He has been a pleasure to work with and we could not have asked for a more professional and hard working manager."
York welcome Shrewsbury Town to Bootham Crescent this weekend.
