The current therapies used to cure diabetes mellitus viz. based on some oral hypoglycemic preparations or insulin are not sufficient and accompany a lot of side effects. Complementary and alternative remedies are being considered in managing diabetes. Therefore, the current study was planned to investigate the anti-diabetic efficacy of Sphaeranthus indicus and Nigella sativa (alone and in combination) in comparison to rational anti-diabetic drug metformin. For this purpose, 54 albino rats were selected and randomly divided into six equal groups after inducing diabetes. Extracts of Sphaeranthus indicus and Nigella sativa were given alone and in combination to animals of three groups, respectively, whereas metformin was administered as standard therapy to animals of the respective group. One group served as positive control while the other one as a negative control. Evaluation criteria were based on serum glucose and insulin levels, oxidative stress biomarkers and gene expression. Provision of respective treatments led to a statistically significant decrease in serum glucose levels and vice versa in serum insulin levels; this change was statistically non-significant among all the treated groups at the end of the study period. A similar trend was observed in the case of oxidative stress biomarkers viz. total oxidative stress and total antioxidant capacity, where the former was decreased and later was increased significantly after provision of treatments. Similarly, the provision of Sphaeranthus indicus and Nigella sativa alone or in combination upregulated the insulin signaling pathway genes while downregulated the genes for MAPK downstream JNK pathway.