Clinical outcomes of BRAF-mutant melanoma patients have significantly improved with combination BRAF and MEK inhibitors (BRAFi/MEKi), which target components of the MAPK/ERK signalling pathway. However, success of targeted therapies in treating metastatic melanoma is hampered by both acquired and inherent drug resistance; mainly contributed by overactivation of the MAPK/ERK pathway. Recently published data from our lab have demonstrated that co-inhibiting CDK4/6 and PRMT5, both downstream of the MAPK/ERK pathway, was an effective therapeutic strategy in BRAF-mutant melanoma. Hence, we hypothesised that BRAFi-resistant melanoma cells would also respond to the dual inhibition of CDK4/6 and PRMT5, considering CDK4/6 and PRMT5 lie downstream of the activating events that lead to BRAFi/MEKi-resistance. Through dose-response assays, we found that melanoma cells that have increased resistance to BRAFi remain sensitive to CDK4/6 inhibitors (CDK4/6i) and PRMT5 inhibitors (PRMT5i). More importantly, co-inhibiting CDK4/6 and PRMT5 suppressed cell proliferation in resistant cells, irrespective of p53 status. Only in p53 wild-type (p53WT) cells did shRNA knockdown of p53 restore their ability to proliferate in the presence of both a CDK4/6 and PRMT5 inhibitor, suggesting p53 plays a role in the robust response of p53WT cells to this novel combination. Correspondingly, our whole genome CRISPR/CAS9 knockout screen on p53WT melanoma cells saw p53 and p21 positively enriched after 24 days on PRMT5 drug pressure. Overall, evidence from our studies support the functional cooperativity of CDK4/6i and PRMT5i as a combination therapy, which exert their effects through p53-dependent and independent mechanisms, thus serving as a potential treatment strategy for BRAF-mutant melanoma patients that either have primary resistance or acquired resistance to BRAFi/MEKi.