Objective To investigate the effect of the combination of pembrolizumab and chemotherapy?regimen of etoposide + cisplatin (EP) on disease control rate and survival rate in patients with small cell lung cancer (SCLC) for a randomized double-blind trial. Methods A total of 94 patients with SCLC admitted to our hospital from March 2020 to April 2023 were selected. According to the random envelope method, they were divided into EP group (n=47) and combined group (n=47). The EP group received EP chemotherapy, and the combination group received additional treatment with pembrolizumab based on the EP group. The clinical efficacy, tumor markers [pro-gastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), carcinoembryonic antigen (CEA)], T lymphocyte subsets (CD3+, CD4+/CD8+, CD4+), serum-related factors [matrix metalloproteinase-9 (MMP-9), transforming growth factor-β1 (TGF-β1), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α)], incidence of toxic and side effects, and survival rate (half a year, one year) were compared between the two groups. Results The disease control rate in the combined group was higher than that in the EP group (P<0.05). There was no significant difference in the incidence of grade I-IV toxic and side effects between the two groups (P>0.05). Compared with the EP group, the combined group had lower levels of ProGRP, NSE, CEA, MMP-9, TGF-β1, IFN-γ, and TNF-α after treatment (P<0.05). After treatment, CD3+, CD4+/CD8+, and CD4+ in both groups were decreased, but the combined group was higher than the EP group (P<0.05). The half-year and one-year survival rates in the combined group were higher than those in the EP group (P<0.05). Conclusion The combination of pembrolizumab and EP chemotherapy for the treatment of SCLC can effectively improve the overall efficacy of patients, reduce tumor marker levels, improve immune function, delay disease progression, and increase long-term survival rate.