Objective: To evaluate the antidiabetic and anti-obesity potentials and the safety of a polyherbal remedy. Method: A mixture of polyherbal remedy containing Gymnema sylvestre, Garcinia cambogia, Cleome droserifolia, and Nigella sativa (100 or 200 mg/Kg, p.o.) was subjected to qualitative chemical identification for marker compounds on individual plant extracts using Q-TOF-LC-MS. In addition, the antidiabetic and anti-obesity potential were evaluated in streptozotocin-induced diabetic rats using metformin (100 mg/Kg, p.o.) and insulin (10 U/Kg, IP) as standards. The evaluation based on fasting blood glucose level (FBG), insulin level, and change in body weight gain of different treatment groups. Furthermore, the safety profile was assessed by the measurement of certain biochemical, hematological, and histopathological parameters. Results: A total of thirteen marker compounds, (Gymnemoside ND1, Myricetin, Hydroxycitric acid lactone, Garcinol, Garcimangosone D, 5,3`-Dihydroxy-3,6,7,4`,5`-pentamethoxyflavone, 5-Hydroxy-3,6,7,3`,4`,5`-hexamethoxyflavone, Magnoflorine, Kaempferol glycoside, Sapindoside B, Alpha-hedrin, Tauroside H2, and Thymoquinone) were identified in the four plant extracts individually. The administration of polyherbal remedy extract (100 or 200 mg/Kg, p.o.)-, metformin-, and insulin-treated diabetic rats resulted in a significant decrease in the FBG by 62, 67, 44 and 73 % respectively, and significant increase in insulin level by 2161, 3433, 2400 and 5658 %, respectively, as compared to vehicle-treated control. Regarding the body weight change, polyherbal remedy extract (100 or 200 mg/Kg, p.o.)-, metformin-, and insulin-treated animals demonstrated a significant decrease by 45, 54, 72 and 65%, respectively, as compared to their initial weight. The results of polyherbal remedy (100 or 200 mg/Kg, p.o.)-treated groups showed a dose-independent potency between that obtained from insulin- and metformin-treated groups. Concerning the safety profile; treatment with remedy extracts markedly improved the streptozotocin-induced alteration in the hepatic biochemical, and hematological indices (liver enzymes, total protein, albumin, TC, TG, HDL, LDL, RBCs count, WBCs count, Hb concentration and platelet count) besides preservation of the normal histopathological features of liver, kidney, and pancreas. Conclusion: The polyherbal remedy can be used as an effective and safe treatment of obesity, diabetes, and its complications.