Tacrolimus (Tac) is an immunosuppressive drug used to reduce the risk of allograft rejection; however, it can induce renal injury. High mobility group box 1 (HMGB-1) protein, which induces inflammation through the aberrant stimulation of the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response protein (MyD88)/nuclear factor kappa B (NF-κB) trajectory, could represent a molecular target for alleviating Tac-induced renal damage. The present study aimed to investigate the potential protective role of the GLP-1 agonist, dulaglutide (Dula), against Tac-induced nephrotoxicity in rats. Rats were administered Tac (5 mg/kg/day) and vehicle or Dula (0.2 mg/kg once a week) for 14 days. Treatment with Dula reduced serum creatinine plus blood urea nitrogen and attenuated Tac-induced renal histopathological changes. Dula treatment also hampered renal inflammation and restored redox homeostasis, as indicated by remarkably reduced tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), malondialdehyde (MDA), and NADPH oxidase 1 levels alongside marked replenishment in reduced glutathione (GSH) content. These effects were mediated through the upregulation of miR-22 expression and the consequent inhibition of the HMGB-1/TLR4/MyD88/NF-κB trajectory. Collectively, Dula has been demonstrated to protect rats against Tac-induced nephrotoxicity by reducing inflammation, restoring redox homeostasis, and modulation of the miR-22/HMGB-1/TLR4/MyD88/NF-κB trajectory. Dula may be beneficial clinically in preventing Tac-induced renal injury.