Objective To investigate the expression of ACTN1 in cutaneous squamous cell carcinoma （CSCC） and its association with clinicopathological features and prognosis. Methods A total of 150 patients with cutaneous squamous cell carcinoma （CSCC） and 100 healthy controls were enrolled in this study. The serum expression levels of ACTN1 were measured using ELISA. All CSCC patients underwent post?surgical follow?up and were categorized into a poor prognosis group （n = 69） and a good prognosis group （n = 81）. Additionally， the 69 patients in the poor prognosis group were further classified into an ACTN1 lower expression subgroup （n = 35） and an ACTN1 higher expression subgroup （n = 34） based on the median expression level of ACTN1. Logistic regression analysis was employed to identify risk factors associated with poor prognosis in CSCC patients. ROC curve analysis was conducted to evaluate the clinical utility of serum ACTN1 expression levels in predicting poor prognosis in CSCC patients. Kaplan?Meier （K?M） survival analysis was utilized to assess the relationship between serum ACTN1 expression levels and the median time to poor prognosis in the 69 patients with poor prognosis. Furthermore， 40 additional CSCC patients were recruited to compare the expression levels of ACTN1 in CSCC tissues and adjacent tissues using immunohistochemistry. Results The serum expression levels of ACTN1 in the Control group and the CSCC group were （12.12 ± 2.26） ng/mL and （4.56 ± 1.02） ng/mL， respectively. Compared to the Control group， the serum expression level of ACTN1 in the CSCC group was significantly decreased， and the difference was statistically significant （t = 31.37， P < 0.001）。 In the poor prognosis group， the proportion of tumors with a diameter ≥ 5 cm， low degree of tumor cell differentiation， subadipocyte invasion depth， lymph node metastasis incidence， and serum ACTN1 expression levels were all significantly higher compared to the good prognosis group， with statistical significance （P < 0.05）. Logistic regression analysis revealed that lymph node metastasis （OR = 3.253） and elevated ACTN1 expression （OR = 2.894） were independent risk factors for poor prognosis following CSCC surgery. The area under the curve （AUC） for serum ACTN1 expression in predicting poor prognosis post?surgery in CSCC patients was 0.911. At a cut?off value of 13.19 ng/mL for ACTN1， the diagnostic sensitivity and specificity were 89.78% and 92.12%， respectively. The median time to poor prognosis was 25 months in the ACTN1 low?expression group and 18.5 months in the ACTN1 high?expression group， respectively. The median time to poor prognosis was significantly shorter in the ACTN1 high?expression group compared to the low?expression group （HR = 6.627， P < 0.001）. Among 40 CSCC tissue samples， 32 cases exhibited higher ACTN1 expression， while 8 cases showed lower expression. In contrast， among 40 paracancerous tissue samples， 11 cases had higher ACTN1 expression and 29 cases had lower expression. The higher expression rate of ACTN1 in CSCC tissues was significantly elevated compared to paracancerous tissues （χ² = 22.175， P < 0.001）. Conclusion The serum expression level of ACTN1 in CSCC patients was significantly elevated， suggesting its potential as a biomarker for assessing post?surgical prognosis in CSCC patients.