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It remains unclear whether and how harmful metabolites compromise lysosome function in the etiopathology of metabolic disorders. Combining Caenorhabditiselegans and mouse models, we demonstrate that homocysteine, an intermediate in methionine-cysteine metabolism and the cause of the life-threatening disease homocystinuria, disrupts lysosomal functions. In C. elegans, mutations in cystathionine \u03b2-synthase cause strong buildup of homocysteine and developmental arrest. We reveal that homocysteine binds to and homocysteinylates V-ATPase, causing its inhibition and consequently impairment of lysosomal degradative capacity. This leads to enormous enlargement of lysosomes with extensive cargo accumulation and lysosomal membrane damage in severe cases. Cbs-deficient mice similarly accumulate homocysteine, displaying abnormal or damaged lysosomes reminiscent of lysosomal storage diseases in multiple tissues. 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