African swine fever virus (ASFV) encodes more than 150 proteins, most of them of unknown function. We used a high-throughput proteomic analysis to elucidate the interactome of four ASFV proteins located at the inner viral membrane of the virion. These proteins mediate a critical step of the infection cycle, the fusion and endosomal exit of the virions. Using affinity purification and mass spectrometry, we were able to identify potential interacting partners for ASFV proteins P34, E199L, MGF360-15R and E248R. Representative molecular pathways for these proteins were intracellular and Golgi vesicle transport, endoplasmic reticulum organization, lipid biosynthesis, and cholesterol metabolism. Some of these proteins shared interacting partners, suggesting potential common functions. Rab proteins geranyl geranylation emerged as a significant hit, interactor of both p34 and E199L. Our results point out that ASFV fusion proteins could act coordinately to ensure a tight regulation of the endocytic pathway, and the molecular exchange at ER membrane contacts. Membrane trafficking and lipid metabolism were important categories as we found significant interactions with several enzymes of the lipid metabolism. These targets were confirmed using specific inhibitors with antiviral effect in cell lines and macrophages.