Objective To investigate the short-term efficacy and toxicity of penpulimab combined with chemotherapy in the treatment of metastatic or locally advanced squamous non-small cell lung cancer (NSCLC).Methods The study included patients with metastatic/locally advanced squamous NSCLC and admitted to our hospital between October 2021 and August 2022. These patients were randomly assigned into two groups, each containing 62 cases. Patients in control group received chemotherapy, while those in observation group received chemotherapy combined with penpulimab. Compare the short-term efficacy, immune factors before and after treatment, levels of lung cancer-related tumor markers, and survival time between the two groups, as well as the occurrence of adverse reactions in both groups.Results In the observation group, there was 1 case of complete response (CR) and 32 cases of partial response (PR), resulting in an overall response rate (ORR) of 53.22%. In the control group, there were only 23 cases of PR, with an ORR of 37.10%. The incidence of reactive capillary proliferation and hypothyroidism was significantly higher in the observation group than in the control group (P<0.05). The post-treatment immune function indicators (CD3⁺, CD4⁺, CD4⁺/CD8⁺, CD8⁺) and tumor marker levels (CYFRA21-1, CEA, and VEGF) were improved much more in the observation group than in the control group (all P<0.05). All patients were followed for 2 years, and no patients were lost in the follow-up. The OS [ (20.41±0.25) months] and PFS[ (18.84±0.46) months] of patients in the observation group were both longer than in the control group (P<0.05).Conclusion Penpulimab combined with chemotherapy can prolong the survival time of metastatic/locally advanced squamous NSCLC patients, improve their immune function and down-regulate their levels of tumor markers.