Background: To determine the differences in efficacy and safety between drug-eluting bead bronchial arterial chemoembolization (DEB-BACE) combined with intravenous chemotherapy and systemic chemotherapy alone for the treatment of stages III and IV lung squamous cell carcinoma (LSCC). Methods: 136 patients with stages III and IV LSCC were retrospectively recruited between January 2018 and August 2021 and divided into group A (chemotherapy-only, N = 95) and group B (DEB-BACE combined with intravenous chemotherapy, N = 41). The short-term efficacy, hemoptysis and dyspnea remission rates, and incidence of adverse reactions were compared between the two groups. Survival estimation was performed by Kaplan-Meier, and the Log-rank test was performed to compare survival differences between groups. Results: The One-month DCR (90.2% vs. 49.5%) and ORR (75.6% vs. 38.9%) were better in group B than in group A (both P < 0.05). Progression-free survival (PFS) was 8.0 months in Group B and 6.0 months in Group A, a statistically significant difference (P < 0.05). The PFS rates at 6, 12, and 24 months were 63.4%, 24.4%, 0.0%, 43.2%, 13.7%, and 0.0% in groups B and A, respectively, this difference was significant (P < 0.05). The median overall survival was better in group B than in group A (19.0 vs 14.0 months, P < 0.05). The OS rates at 6, 12, and 24 months were 100%, 85.4%, 26.8%, 78.9%, 56.8%, and 22.1% in groups B and A, respectively, with statistically significant differences (P < 0.05). The hemoptysis and dyspnea remission rates were better in group B than in group A within one month after treatment (P < 0.05), however, in terms of the incidence of adverse reactions, incidences, such as post-treatment fatigue and bone marrow suppression, were significantly lower in Group B than in Group A during the follow-up period (P < 0.05). Conclusions: DEB-BACE combined with intravenous chemotherapy is effective for the treatment of advanced LSCC, with lower adverse reactions, and significant improvement in patients' hemoptysis and dyspnea symptoms, which is worthy of clinical application.