The motion of the Adriatic microplate is thought to be highly sensitive to the surrounding subduction zones and the convergence of Africa and Eurasia. However, our understanding of the mantle dynamics in the Mediterranean region and its effect on plate motion remains incomplete. Here, we present a large set of 3D thermomechanical models of the entire Mediterranean region over the last 35 Myr to understand what controls the motion of the Adriatic microplate. The simulations take the convergence of the African and Arabian plates with the Eurasian plate into account, along with the dynamics of the subduction systems in the western (Apennines-Calabria), central (Dinarides-Hellenides) Mediterranean and in the Alpine-Carpathian region. Our results demonstrate that the subduction systems around Adria are highly coupled, which gives rise to complex asthenospheric flow in the central Mediterranean. We find that the plate motion of the Adriatic microplate over the last 35 Myr is controlled by interplay of three main factors: 1) the convergence between the African and Eurasian plates, 2) the retreat of the Alpine subduction zone to the north of Adria, and 3) the distance between the Calabrian and Hellenic subduction zones around Adria. Furthermore, in a system characterized by active convergence between Africa and Eurasia, the slab pull exerted by nearby subduction zones can only notably influence the motion of the Adriatic microplate if these subduction zones are located within a few hundred kilometers of Adria.