Great advances have been made in malignant melanoma treatments, whereas drug resistance still limits many drug applications. CRKL has been reported to be overexpressed in various tumors and showed poor prognosis. However, its specific function and mechanism in melanoma remain unclear. In the present study, we investigated the expression of CRKL and its clinical association by bioinformatics and clinical analysis, and then performed a series of in vitro and in vivo experiments to demonstrate its function and mechanism. Results showed that CRKL increased during melanoma progression and was strongly associated with poor prognosis. CRKL silencing effectively inhibited melanoma cell growth and invasion via ERK/MMP9 and PI3K/AKT signaling pathways both in vitro and in vivo. Moreover, CRKL silencing induced pyroptosis in melanoma cells by upregulating the levels of pyroptosis-associated proteins, such as NLRP3, cleaved Caspase-1, and GSDMD-N. Importantly, our study demonstrated that interfering with CRKL expression enhanced the chemotherapy sensitivity of melanoma cells to cisplatin by regulating PI3K/AKT and NLRP3/GSDMD signaling pathways. In conclusion, our study uncovers a novel molecular mechanism by which CRKL functions in melanoma and highlights potential therapeutic strategies for improving chemotherapy sensitivity in melanoma patients.