Sinonasal squamous cell carcinoma (SNSCC) is an aggressive cancer affecting the nasal and sinus regions, with its progression factors, particularly genetic ones, not yet fully understood. Here, we first conducted a retrospective study with 219 SNSCC patients to identify clinical factors affecting SNSCC prognosis. Additionally, we mined a vast literature dataset to uncover genetic factors associated with SNSCC progression. Based on this data, we constructed SNSCC prognosis pathways and performed a gene set enrichment analysis (GSEA). Clear operative margins were linked to a 73.5-86.3% improvement in overall survival and a 73.5-88.9% lower risk of recurrence. Nasal cavity-originated cases exhibited a 67.6-97.4% decrease in mortality and an 80.7-96.7% lower recurrence rate. Patients at T1-2 staging had a 65.0-80.6% reduced risk of death and recurrence compared to those at T3 stage. Additionally, we identified 53 genes associated with SNSCC, with 14 also implicated in primary tumor site, T stage, and operative margin. These genes, including EGFR, PIK3CA, ERBB2, PTEN, BCL2, BRAF, KRAS, and PRL, form a complex SNSCC-prognosis pathway and were significantly enriched in 42 KEGG pathways and Gene Ontology (GO) terms (FDR-corrected p-value < 0.001), influencing cell growth, apoptosis, and oncogenic signaling pathways. Our study suggests that three clinical parameters (operative margin type, primary tumor site, and T-stage) and 14 genetic factors may influence SNSCC prognosis post-surgery. These findings deepen our understanding of SNSCC and offer potential avenues to enhance its treatment and outcomes.© 2024. The Author(s).