Melanoma is highly heterogeneous with diverse genomic alterations and partial therapeutic responses. Emergence of drug-resistant tumor cell clones accompanied with high AXL expression level is one of the major challenges for anti-tumor clinical care. Recent studies have demonstrated that high AXL expression in melanoma cells mediated drug-resistance, epithelial-mesenchymal transition (EMT) and elevated survival of cancer stem cells (CSCs). Given that we have identified several non-steroidal anti-inflammatory drugs (NSAIDs) including Aspirin potently induce the degradation of AXL, we questioned whether NSAIDs could counteract the AXL-mediated neoplastic phenotypes. Here we found NSAIDs downregulate PKA activity via the PGE2/EP2/cAMP/PKA signaling pathway and interrupt the PKA-dependent interaction between CDC37 and HSP90, resulting in an incorrect AXL protein folding and finally AXL degradation through the ubiquitination-proteasome system (UPS) pathway. Furthermore, NSAIDs not only sensitized the MEK inhibitor treatment, but also reduced EMT and relapse mediate by AXL in tumor tissue. Our findings suggest that the combination of inhibitors and NSAIDs, especially Aspirin, could be a simple but efficient modality to treat melanoma in which AXL is a key factor for drug-resistance, metastasis, and relapse.