Pancreatic ductal adenocarcinoma (PDAC) remains a formidable clinical challenge. Next-generation protein arginine methyltransferase 5 (PRMT5) inhibitors show promising clinical results in a subset of PDACs with co-deletion of the tumor suppressor CDKN2A with the methylthioadenosine phosphorylase (MTAP) gene. However, primary and secondary resistance mechanisms limit the efficacy of this synthetic lethality approach. Our study reveals that compensatory spliceosomal reprogramming drives adaptation to PRMT5 inhibition in PDAC. Through comprehensive molecular profiling, we demonstrate that PRMT5 inhibitors induce marked upregulation of RNA-binding proteins, particularly RNA-binding protein 39 (RBM39), across diverse preclinical cellular models. We exploit this vulnerability by combining PRMT5 inhibition with Indisulam-mediated RBM39 degradation yielding synergistic activity. The combination strategy significantly enhanced apoptotic cell death and suppressed tumor outgrowth in resistance assays compared to single-agent treatments. We conducted multi-omics analysis revealing concomitant suppression of DNA repair machinery and metabolic pathways. Collectively, our work defines spliceosomal rewiring as a mechanism to limit cellular PRMT5 efficacy and nominates RBM39 as a therapeutically exploitable vulnerability, establishing the mechanistic foundation for dual targeting of the splicing machinery.