Background: The connection between inflammation and hyperglycemia leads to diabetes mellitus and its complications. Nutraceuticals are natural sources which can be used as supplement food for the prevention of many disorders. Our aim was studied to the protective role of two antioxidants (Rutin and Chlorogenic acid) with Spirulina fusiformis (SP) on streptozotocin-induced diabetic rats and being challenged with lipopolysaccharide to accelerate the diabetic inflammation. Materials and Methods: Rats were distributed into eleven groups. Each group has 6 rats. Lipopolysaccharide was administered to induced inflammation in diabetes mellitus rats. Orally administered Spirulina fusiformis (500 and 1000 mg/kg), rutin and chlorogenic acid (30 and 60 mg/kg) individually or in combination for 28 days. Metformin (200 mg/kg) was used as a standard drug. Biochemical parameters, body weight, and blood pressure levels were measured at different intervals. Histological studies, Scanning Electronic Microscopy, and gene expression analysis Real-time polymerase chain reaction of NRF2 and inducible nitric oxide synthase gene were analyzed at the end of the experiment. Results: Decreased in blood glucose levels and lipid profile at different intervals were noted with combination drug therapy (Spirulina fusiformis with rutin and Spirulina fusiformis with Chlorogenic acid). Improvement in antioxidant enzymes and pro-inflammatory cytokines levels were decreased on the 45th day. Maximum diastolic blood pressure levels were decreased statistically on the 45th day. Proof of evidence was also supported with these results. Conclusion: Combination therapy was showed excellent results than individual therapy at all parameters.