Sotetsuflavone (SF) is an antioxidant flavonoid derived from the Cycas thouarsii R.Br. plant. Although SF regulates numerous cellular pathways influencing inflammation, its antiinflammatory benefits against gastric ulcers are less well-studied. Hence, it is imperative to thoroughly understand the potential gastroprotective mechanisms of SF. This study aimed to explore the effectiveness of SF against indomethacin (IND)-induced gastric ulcers. Network analysis and molecular docking were used to identify the specific targets and pathways related to SF and stomach ulcers. To validate the in vivo pharmacological action of SF, 36 rats were divided into six groups. Ulcer index (UI), protective percentage (PP), gastric mucosal mediators, oxidant/antioxidant status, and inflammatory markers (MIF, M-CSF, and AIF-1) were assessed. Additionally, the expression of PI3K, Akt, Siah2, SOCS3, JAK2, and STAT3 was determined. Stomach histopathology and immunohistochemistry were done. Network pharmacology detected 46 overlapping targets between SF and stomach ulcers, with HIF1A as the primary target among the top hubs. The network also revealed that JAK/STAT, PI3K/Akt, and HIF-1A signaling are among the top 50 markedly enriched KEGG pathways. Furthermore, docking results confirmed that SF has a strong binding affinity towards SOCS3, JAK2, STAT3, M-CSF (CSF-1), and AIF-1. Therefore, we hypothesized that the JAK2/STAT3 pathway may be primarily responsible for SF antiinflammatory action. Through up-regulating SOCS3, SF altered the PI3K/Akt pathway, mitigating oxidative stress, blocking the outflow of inflammatory mediators, and impeding gastric ulcer development. Overall, SF, by the SOCS3-mediated JAK2/STAT3 suppression, might considerably reduce oxidative stress, inflammation, and ulceration caused by indomethacin in the stomach.