Abstract: Objective To explore the efficacy of dapagliflozin tablets in the treatment of new-onset type 2 diabetes mellitus(T2DM) with obesity. Methods A total of 98 patients with newly diagnosed T2DM and obesity in Wuhan NO.1 Hospital from January 2023 to January 2024 were randomly divided into two groups, with 49 patients in each, using a random number table. The control group received oral metformin sustained-release tablets, while the intervention group received dapagliflozin tablets in addition to the metformin regimen. Both groups were treated for 12 weeks. The overall response rate after 12 weeks of treatment was recorded for both groups. The levels of fasting plasma glucose(FPG), 2-hour postprandial plasma glucose(2hPG), glycosylated hemoglobin(HbA1c), body mass index(BMI), homeostasis model assessment of insulin resistance(HOMA-IR), serum hypoxia-inducible factor-1α(HIF-1α), and Toll-like receptor 4(TLR4) were compared between and within the two groups at baseline, 8 weeks, and 12 weeks of treatment. The adverse reactions during treatment were also compared. Results One patient withdrew from the control group, and 2 patients withdrew from the intervention group, resulting in 48 patients in the control group and 47 patients in the intervention group for final analysis. The overall response rate in the intervention group was higher than that in the control group(P< 0.05). The levels of FPG, 2hPG, HbA1c, BMI, HOMA-IR, HIF-1α and TLR4 in the two groups decreased after 8 and 12 weeks of treatment compared with baseline(P< 0.05). After 12 weeks of treatment, the levels of FPG, 2hPG, HbA1c, BMI, HOMA-IR, HIF-1α and TLR4 were lower than those after 8 weeks of treatment in both groups(P< 0.05). At both 8 and 12 weeks after treatment, these parameters in the intervention group were lower than those in the control group(P< 0.05). No statistically significant difference was found in the incidence of adverse reactions between the two groups during treatment(P> 0.05). Conclusion Dapagliflozin tablets demonstrate significant therapeutic effects on new-onset T2DM with obesity, improving insulin resistance. The mechanism may be related to the downregulation of the HIF-1α/TLR4 pathway expression.