Objective To analyze the correlation between the expression of fibroblast growth factor 9 (FGF9), SMAD2 and clinicopathological features, prognosis in patients with non-small cell lung cancer (NSCLC). Methods Seventy-five patients with NSCLC admitted to our hospital from January 2018 to December 2020 were selected as the study subjects. The tumor tissues and adjacent tissues were collected during surgical resection. The expression of FGF9 and SMAD2 proteins in cancer tissues and adjacent tissues was compared by immunohistochemistry. The patients were grouped into FGF9 negative expression group, FGF9 positive expression group, SMAD2 negative expression group and SMAD2 positive expression group according to the expression of FGF9 and SMAD2 in cancer tissues. The clinicopathological characteristics were compared between the two groups. The expression correlation between FGF9 and SMAD2 was analyzed by spearman method. KM curve was constructed to analyze the relationship between the expression of FGF9, SMAD2 and survival time; COX regression analysis was applied to analyze the risk factors of poor prognosis in NSCLC patients. Results Compared with the adjacent tissues, the positive rates of FGF9 and SMAD2 in NSCLC tissues were higher (P<0.05). There was significant difference in the positive expression rate of FGF9 between TNM I+II and TNM III NSCLC patients (P<0.05). Whether lymph node metastasis, TNM I+II and TNM III, and the positive expression rate of SMAD2 in patients with moderately differentiated and poorly differentiated NSCLC were significantly different (P<0.05). The expression of FGF9 and SMAD2 in NSCLC was positively correlated (r=0.281, P<0.05); during the follow-up period, the cumulative survival rate (20.8%) in FGF9 positive expression group was lower than that in negative expression group (77.3%). The cumulative survival rate of patients in positive SMAD2 expression group (25.9%) was lower than that of patients in negative SMAD2 expression group (76.5%) (P<0.05). The progression-free survival rate (9.4%) in the FGF9 positive expression group was lower than that in the negative expression group (63.6%), and the progression-free survival rate (15.5%) in the SMAD2 positive expression group was lower than that in the negative expression group (58.8%), and the difference between groups was statistically significant. TNM staging, positive expression of FGF9 and positive expression of SMAD2 were risk factors for poor prognosis in NSCLC patients (P<0.05). Conclusion The positive expression of FGF9 and SMAD2 is increased in NSCLC, and they are related to the clinicopathological characteristics and prognosis of patients, FGF9 and SMAD2 may jointly participate in the cancer progression of NSCLC