The TGF-β1/Smad signaling pathway, particularly Smad2 and Smad3 mediate pro-fibrotic responses, while Smad7 exerts inhibitory effects.<h4>Aim</h4>The study aimed to evaluate the therapeutic potential of paraxanthine (Para), an active caffeine metabolite, and azilsartan (Azil), an angiotensin II receptor blocker, in attenuating gentamicin (GM)-induced renal fibrosis through targeting Smad pathway and miRNA-21/200b.<h4>Methods</h4>Seventy male albino mice were randomized into seven groups (n = 10): Control, GM, SIS3 + GM, Para + GM, Azil + GM, Para + SIS3 + GM, and Azil + SIS3 + GM. Here, SMAD2 is linked to renal fibrosis.