ABSTRACT: Cinobufotalin injection is a water-soluble preparation extracted from the skin secretion of Bufo bufo gargarizans Cantor or B. melanotictus Schneider, which has been widely used as an adjuvant treatment in lung cancer patients. This study aimed to evaluate the clinical efficacy and safety of cinobufotalin (PubChem CID: 259776) injection as an adjunctive treatment for lung cancer. We designed a meta-analysis that performed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We aim to include randomized controlled trials by systematically searching the PubMed, EMBASE, CNKI, Wanfang database, VIP, CBM, the Cochrane Central Register of Controlled Trials, and Chinese Clinical Trial Registry from inception to Mar 1, 2020, comparing the difference between the use of cinobufotalin injection as an adjunctive treatment and a control group without cinobufotalin injection. The objective response rate (ORR) and quality of life (QOL) will be defined as the primary outcomes, and the disease control rate (DCR) and adverse events will be defined as the secondary outcomes. We included 21 articles with 1735 cases of lung cancer patients. Comparison results show that combining with cinobufotalin injection can improve ORR (OR?=?1.77, 95% CI [1.43, 2.21], P?P?=?0.94, I 2?=?0%); DCR (OR?=?2.20, 95% CI [1.70, 2.85], P?P?=?0.60, I 2?=?0%); KPS score (OR?=?3.10, 95% CI [2.23, 4.32], P?P?=?0.85, I 2?=?0%); and the effect of pain relief (OR?=?2.68, 95% CI [1.30, 5.55], P?=?0.008), with low heterogeneity (P?=?0.72, I 2?=?0%). Low-to-moderate evidence shows that cinobufotalin injection combined with chemotherapy can significantly increase ORR, DCR, QOL, and the effect of pain relief. Meanwhile, cinobufotalin injection did not bring additional adverse events such as hematological toxicity, gastrointestinal toxicity, cardiotoxicity, hepatotoxicity, and nephrotoxicity; however, multicenter, large-sample, high-quality clinical research results are still needed to reveal the therapeutic effect of cinobufotalin injection in small-cell lung cancer (PROSPERO registration number: CRD42020170052).