Background: In recent years, the morbidity of gestational diabetes (GD) has increased by around 5%–10%, and it now affects around 8%–21% of all births, with around 3%–5% of these women suffering from long-term diabetes after birth. Premature maturation, birth trauma, macrosomia, and respiratory problems are the common complications seen in pregnant women with GD. Lack of glucose tolerance is normally found in pregnant women with GD. Furthermore, GD during pregnancy can result in more complications in the long run, with a high risk of type-2 diabetes developing in subsequent generations. Materials and Methods: C57BL/KsJ mice were used to evaluate the efficacy of oridonin against GD. The animals were divided into four groups: normal mice with pregnancy, GD alone; GD + oridonin (25 mg/kg bw), and GD + oridonin (50 mg/kg bw). After 10 days of gestational period, the following parameters were evaluated: glucose and insulin tolerance in blood, body weight, lipid peroxidation products (thiobarbituric acid reactive substances (TBARS)), and antioxidant markers (superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) in liver tissues were analyzed. After 20 days of gestational period, the following parameters were measured in the liver tissues by using ELISA kits: elevation of secreted protein acidic and rich in cysteine (SPARC) and pro-inflammatory cytokines. Results: In GD-induced mice, oridonin partially corrected glucose and insulin tolerance and maintained ideal body weight. Moreover, oridonin elevated the levels of SOD, CAT, and GSH and reduced the levels of TBARS in GD mice. Finally, oridonin downregulated the expression of SPARC and nuclear factor kappa B (NF-κB). Conclusion: In summary, oridonin showed an anti-inflammatory antioxidant effect and prevented GD in pregnant mice.