The 51-year-old leaves the club in seventh place on the standings, with 56 points, three adrift of city rivals Milan and the final Europa League qualifying place.
This follows a poor run of form that has seen the Nerazzurri pick up just one point from their last six games.
Stefano Vecchi has been appointed to the position as the club searches for a new head coach with Chelsea's Antonio Conte, Atletico Madrid's Diego Simeone and AS Roma's Luciano Spalletti three names already being put forward as potential replacements for Pioli.
A brief statement from the club read: "F.C. Internazionale Milano announces that it has parted ways with head coach Stefano Pioli and his technical staff.
"Inter thanks Stefano and his team for the dedication and hard work carried out at the club over the last six months in what has proven to be a difficult season.
"Primavera coach Stefano Vecchi will take charge of the first team immediately and for the remaining three matches of this season. The club will begin planning now for the next season."
Pioli has managed a number of clubs including Chievo, Palermo, Bologna and Lazio, and took over at Inter on 8 November 2016 on an 18-month contract following Frank de Boer's sacking.