<p>Small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) are the two main types of lung cancer. Signal transducer and activator of transcription 3 (STAT3) plays an oncogenic role in various malignancies, including lung cancer, and targeting STAT3 is currently being considered as a potential therapeutic approach. The expression of p-STAT3, STAT3, p-SRC, SRC, and apoptosis- and mitochondrial fission–related proteins was assessed through western blot analysis. The cellular events including cell proliferation, apoptosis and cell cycle, and cisplatin resistance were assessed via CCK8, colony formation assays, and flow cytometry. Mitochondrial oxidative stress was measured by DCFH-DA, JC-1, and oxygen consumption rate (OCR) kits. Network pharmacology combined with molecular docking was used to investigate the molecular targets of STAT3 inhibitor SH-4–54 in the treatment of SCLC. Xenograft mouse models were constructed to verify the in vivo impacts of SH-4–54, and related biochemical parameters were analyzed. STAT3 phosphorylation was upregulated in SCLC. The STAT3 inhibitor SH-4–54 inhibited cell proliferation, promoted cell apoptosis, induced cell cycle arrest, decreased cisplatin resistance, and reduced oxidative phosphorylation in mitochondria of SCLC cells. Additionally, it inhibited tumor growth in tumor-bearing mice. SRC functioned as a core target of SH-4–54, and its phosphorylation level was decreased by SH-4–54. YEEI peptide, an SRC activator, could reverse the in vitro impacts of SH-4–54 on ROS production, cell proliferation, apoptosis, and cell cycle. Our findings demonstrate that the STAT3 inhibitor SH-4–54 can target SRC to suppress the tumorigenesis and oxidative phosphorylation in SCLC.</p>