Drugs that selectively kill senescent cells, senolytics, can improve the outcomes of cancer, fibrosis and age-related diseases. Despite their potential, our knowledge of the molecular pathways that affect the survival of senescent cells is limited. To identify novel senolytic targets, we performed RNAi and CRISPR screens and identified COPI (Coatomer Complex I)vesicle formation as a liability of senescent cells. Genetic or pharmacological inhibition ofCOPI results in Golgi dispersal, intracellular accumulation of secreted factors, and unfolded protein response-dependent cell death of senescent cells. Knockdown of COPI subunits improves the outcomes of cancer and fibrosis in mouse models. Drugs targeting COPI have poor pharmacological properties, but N-myristoyltransferase inhibitors (NMTi) phenocopy COPI inhibition and are potent senolytics. NMTi eliminate senescent cells, ameliorating lung fibrosis and liver steatosis in aged mice. Our results suggest that senescent cells rely on a hyperactive secretory apparatus, and that inhibiting trafficking kills senescent cells in various senescence-associated diseases and during ageing.