Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Despite advances in targeted therapy and immunotherapy, the prognosis of advanced NSCLC remains poor, highlighting the need for novel therapeutic targets. Plant homeodomain finger protein 20 (PHF20), an epigenetic reader, has been implicated in tumor progression; however, its stability regulation remains largely unknown. In this study, we aimed to identify a deubiquitinating enzyme (DUB) regulating PHF20 stability in NSCLC. A DUB overexpression screen was performed, followed by CRISPR/Cas9-mediated knockout validation and functional analyses. We identified DUBX as a candidate regulator of PHF20 stability. DUBX depletion accelerated PHF20 degradation, while MG132 treatment partially restored PHF20 levels, suggesting involvement of the proteasomal pathway. Ubiquitination assays were performed to investigate PHF20 lysine residue(s) involved in DUBX-mediated regulation. Furthermore, DUBX depletion suppressed NSCLC cell proliferation and colony formation. Bioinformatics analyses of clinical datasets demonstrated associations of PHF20 and DUBX expression with overall survival (OS) and disease-free survival (DFS). Collectively, our findings identify DUBX as a novel regulator of PHF20 protein stability and suggest that the DUBX–PHF20 axis may contribute to NSCLC progression and represent a potential therapeutic target.