The success of chemotherapy could be jeopardised by the appearance of senescence in the tumor microenvironment. Transiently, senescence acts as a barrier to tumour progression but persistent accumulation drives pathological inflammation and tumour relapse. A novel and promising therapeutic intervention could be to combine conventional anti-cancer treatments with senolytic agents. In a new research line for our group, we investigated the application of animal venoms and venom-derivatives as “senotherapies”, a new class of senolytics and thus a novel therapeutic approach in cancer. We identified a toxin with senolytic properties (aka venom-senolytic). Our venom-senolytic, along with its optimised analogue, showcased selectivity towards various senescent cancer cells chemically induced by diverse senescence-stimuli. The observed selectivity was mediated by specific lipid-interactions in senescent cancer cells. Mechanistically, we demonstrated that the venom-senolytic induced a marked potassium efflux, which hyperpolarized the plasma membrane of senescent cells. Metabolic examination further revealed a sustained decrease in mitochondrial respiration, which was accompanied by mitochondrial depolarization and cell death. Multi-omics analysis highlighted the impact of our venom-senolytics in metabolism and cancer signalling, including on lipid pathways with structural and inflammatory roles. The modified venom-senolytic strongly synergized with the CDK4/6 inhibitor palbociclib for remission of solid tumours in both mice and zebrafish xenograft melanoma models. Our findings, introduce “senotoxins”: a novel class of potent senolytic agents with promising potential in cancer therapy.