Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality. Despite advancements in gene targeted therapies and immunotherapies, high heterogeneity contributes to limited efficacy and therapeutic resistance. Ubiquitination, a crucial post-translational modification that regulates protein stability and degradation, plays a significant role in cancer pathogenesis by influencing key oncogenic pathways and tumour progression. This review systematically explores the ubiquitin-proteasome system (UPS) and its potential as a therapeutic target for NSCLC. We highlight recent preclinical and clinical studies focusing on ubiquitination-related biomarkers, drug targets and emerging therapies like proteasome inhibitors and Proteolysis-targeting chimeras (PROTACs). By exploring the impact of the UPS on tumour biology, the progression of NSCLC and its response to therapy, we aim to underscore the potential of targeting the ubiquitination-deubiquitination system as a complementary or synergistic approach to existing therapeutic strategies in NSCLC, thereby enhancing patient outcomes and overcoming treatment resistance.