Background Steroid-induced hyperglycemia (SIH) is one of the most important side effects of glucocorticoids. Colchicine is a medication used to manage inflammation with not yet fully understood mechanisms. This work aimed to investigate the potential protecting effect of colchicine against the development of SIH, and to spot the possible mechanisms involved in this action. Methods: 24 adults male Wistar rats were allocated into 4 equal groups; the Control group: obtained saline, the Colchicine Group: received oral colchicine (0.5mg/kg/day) for 10 days, the SIH group: received dexamethasone (1mg/Kg/day, i.p.) for 10 days, the Colchicine-treated SIH Group: received dexamethasone for 10 days simultaneous with colchicine in the same previous doses. At the end of our experimental period, HOMA-IR, serum levels of insulin, and glucose were measured. Also, NLRP-3, ASC, gasdermin, IL-1, caspase-1, 8-OHdG, mTOR, TGF-β1, and Smad-2 were evaluated. Furthermore, histopathology of the liver and pancreas was assessed. Results: Our study detected steroid-induced hyperglycemia with inflammation, oxidative stress, and deteriorated liver and pancreas structure. Treatment with colchicine greatly suppressed the NLRP3/ASC/gasdermin/IL-1/caspase-1 pathway. Moreover, colchicine declined TGF-β1, and Smad2 gene expression with normalization of glycemic parameters and histopathological disruption. Conclusion: according to our findings, colchicine is proposed as a potential inhibitor of SIH.