Background. Gestational diabetes mellitus (GDM) is a significant pregnancy complication characterized by elevated blood glucose levels. This condition arises from insulin resistance and impaired glucose metabolism during the gestational period. In this experimental study, we investigated the protective effect of avicularin against streptozotocin (STZ)-induced GDM in rats and explored the underlying mechanism. Material and methods. Female Swiss Wistar rats were utilized in this study. Gestational diabetes mellitus (GDM) was induced in the rats through the administration of 25 mg/kg streptozotocin (STZ). The rats received oral administration of avicularin at doses of 5, 10, and 15 mg/kg. Body, placental, and fetal weights were measured. Blood glucose levels (BGL) and plasma insulin were assessed at various time intervals. Levels of glycogen, glycated hemoglobin (HbA1c), hemoglobin (Hb), visfatin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), antioxidants, lipids, inflammatory cytokines, apoptotic markers, and inflammatory parameters were evaluated. Additionally, mRNA expression was analyzed in hepatic tissue. Results. Avicularin significantly (p < 0.001) improved the body weight, fetal body weight and reduced the placental weight. Avicularin significantly (p < 0.001) suppressed the elevated blood glucose level and improved the plasma insulin level. Avicularin significantly (p < 0.001) altered the levels of HbA1c, Hb, visfatin, ICAM-1, VCAM-1, LPO, CAT, GSH, GPx, SOD, GST, TNF-alpha, IL-1 beta, IL-6, Il-8, IL-10, IL-18, COX-2, PGE2, iNOS, NF-kappa B, Bax, Bcl-2, Bcl-2:Bax ratio and caspase-3 parameters. Avicularin treatment significantly (p < 0.001) suppressed the mRNA expression of TRL4, MyD88, NF-kappa B, NLRP3, RAGE, VCAM-1, MCP-1, VEGF, Nox2, and p65. Conclusion. The results of this study demonstrated the protective effect of avicularin against streptozotocin-induced gestational diabetes mellitus via modulation of the TLR4/MyD88/NF-kappa B and Bax/Bcl-2/Caspase pathways.