The 67-year-old former Wimbledon and Magpies manager has suffered with long-term health problems, but the club have not commented on the circumstances of his departure at this stage.
A brief statement on their official website read: "Newcastle United can confirm that Joe Kinnear has this evening resigned from his position as director of football with immediate effect. The club will be making no further comment."
Kinnear's unpopular return to St James' Park in 2013 was followed by criticism from the Geordie faithful after the club chose not to make a permanent signing in his first summer heading the player recruitment team.
The sale of star asset Yohan Cabaye to Paris Saint-Germain, and Newcastle's failure to replace him in the January transfer window, resulted in further questions being asked of his capability.
Kinnear, whose relationship with Magpies boss Alan Pardew was believed to be frosty, failed to spend a single penny of Newcastle's money in his role as director of football.