Lung squamous cell carcinoma (LUSC) represents a significant challenge in oncology, necessitating the identification of novel prognostic markers and therapeutic targets. This study is aimed at investigating the oncogenic role of MXD3 (MAX Dimerization Protein 3) in LUSC and its implications for patient prognosis. A retrospective cohort of 199 LUSC patients from the 905th Hospital of People's Liberation Army Navy was analyzed to evaluate MXD3 expression levels and their association with clinicopathological characteristics and survival outcomes. Immunohistochemistry (IHC) staining was performed to assess MXD3 expression in LUSC tissue samples. Survival analyses, including the Kaplan-Meier curves and multivariate Cox regression, were conducted to determine the prognostic significance of MXD3 expression and other clinicopathological factors. Additionally, the methylation status of MXD3 was examined using data from the TCGA database to assess its role in regulating MXD3 expression and survival outcomes. MXD3 expression exhibited significant heterogeneity among LUSC patients, with high MXD3 expression correlating with advanced tumor differentiation grade, larger tumor size, and advanced T and N stages. The Kaplan-Meier survival analyses revealed that high MXD3 expression was associated with shorter cancer-specific survival. Multivariate Cox regression identified MXD3 expression level and lymph node involvement (N stage) as independent prognostic factors for cancer-specific survival in LUSC patients. Additionally, analysis of MXD3 methylation revealed significantly lower methylation levels in LUSC tissues, and reduced methylation correlated with poorer survival outcomes. Our findings highlight MXD3 as a promising prognostic biomarker for LUSC, with high MXD3 expression predicting poorer survival outcomes. MXD3 expression level, along with lymph node involvement and methylation status, could serve as independent prognostic indicators for risk stratification and treatment decision-making in LUSC patients. Further research is warranted to elucidate the underlying mechanisms of MXD3-mediated tumorigenesis and its potential as a therapeutic target in LUSC management.