The success of targeted therapies such as BRAF and MEK inhibitors (BRAFi/MEKi) remain hampered by the emergence of drug resistance, often contributed by the reactivation of the MAPK/ERK pathway. This necessitates the discovery of novel drug targets to improve melanoma patient outcomes, especially those who do not or no longer respond to combination BRAFi/MEKi. PRMT5 is an emerging target for the treatment of cancer, given its overexpression in multiple cancer types including melanoma which correlates with poorer patient prognosis. As a protein arginine methyltransferase, PRMT5 catalyses the methylation of both histone and non-histone proteins, thereby regulating various cellular processes epigenetically. Given that both PRMT5 and CDK4/6 lie downstream of activating events that lead to BRAFi/MEKi-resistance, we sought to investigate the efficacy of this combination treatment in BRAFi/MEKi-resistant melanoma. Indeed, co-inhibiting CDK4/6 and PRMT5 in BRAFi/MEKi-resistant melanoma was effective in vitro and in vivo. Mechanistically, PRMT5 inhibition in melanoma results in the loss of full length MDM4 through alternative splicing, leading to reactivation of the p53 pathway. However, PRMT5 inhibition also harbour p53-independent effects, considering its effectiveness in p53-mutant melanoma cell lines. Through a whole genome CRISPR/CAS9 knockout screen with the PRMT5i, multiple components of the SAGA complex, particularly from its acetyltransferase module, were enriched. These findings were validated when knockout of these SAGA components conferred resistance to the PRMT5i, suggesting an interplay between the SAGA complex and the robust response to PRMT5i which requires further investigation. Nevertheless, evidence from our studies support the functional cooperativity of CDK4/6i and PRMT5i as a combination therapy, which can exert their effects through p53-dependent and independent mechanisms. Thus, co-inhibiting CDK4/6 and PRMT5 may serve as a potential treatment strategy for BRAF-mutant melanoma patients who are resistant to BRAFi/MEKi.