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The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome‐dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin‐3 and K63‐linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy‐dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 suppresses tumor growth and lung metastasis, and enhances the effect of BRAFV600E inhibition. Thus, we demonstrate critical roles of CCDC50‐mediated clearance of damaged lysosomes in supporting tumor growth, hereby identifying a potential therapeutic target of melanoma. Synopsis: CCDC50 acts as a lypophagy receptor, monitors lysosomal damage induced by metabolic stresses, and clears damaged organelles, which reduces ROS accumulation and supports tumor growth. CCDC50 recognizes and delivers damaged lysosomes to autophagosomes for degradation.The timely clearance of damaged lysosomes by CCDC50‐mediated lysophagy contributes to tumor maintenance and progression.A combination of CCDC50 interference and BRAF inhibitor treatment shows an additive effect on the regression of xenografted tumors. [ABSTRACT FROM AUTHOR]