This study investigates the comparative antifibrotic and anti-inflammatory effects of metformin and canagliflozin in lung fibrosis models, focusing on the potential effect of canagliflozin to mitigate fibrosis-related molecular and histopathological changes. Aim: To evaluate the efficacy of metformin and canagliflozin in mitigating lung fibrosis and associated pulmonary complications in rat models by assessing their effects on SMAD2/3 signaling pathways, inflammatory markers, oxidative stress parameters, and histopathological alterations. Methods: This study utilized 40 adult male albino rats, divided into four groups: normal control, lung fibrosis control, metformin-treated lung fibrosis, and canagliflozin-treated lung fibrosis. Lung fibrosis was induced by intratracheal instillation of bleomycin. Treatments included oral metformin (50 mg/kg/day) or canagliflozin (40mg/kg/day) for 14 days. Biochemical parameters, including fasting blood glucose (FBG), advanced glycation end products (AGE), lactate dehydrogenase (LDH), and protein content in bronchoalveolar lavage fluid (BALF), were measured. Histopathological and immunohistochemical analyses were performed on lung tissues to evaluate fibrosis markers, such as TGF-β expression and SMAD2/3 signaling. Results: The current study revealed significant pathological changes in the lung fibrosis control group compared to the normal control group across multiple parameters, including increased SMAD2/3 expression, AGEs, RAGE, MDA, protein, LDH, WBC counts, and lung weight, along with decreased SOD levels. These findings underscore the role of oxidative stress, inflammation, and fibrosis in lung fibrosis pathology. Treatment with Metformin and Canagliflozin significantly mitigated these changes, with both drugs reducing SMAD2/3, AGEs, RAGE, MDA, LDH, and WBC counts, while restoring SOD levels and reducing lung weight. Metformin demonstrated slightly stronger effects in reversing fibrosis, as reflected in histopathological staining and lung weight reduction, aligning with its known antifibrotic and anti-inflammatory properties. Metformin and Canagliflozin also exhibited differences in their systemic effects. Metformin-treated rats showed significant weight loss, potentially due to its metabolic effects, while Canagliflozin-treated rats maintained body weight closer to normal. Both treatments effectively reduced inflammatory and fibrotic markers, as shown by immune and Masson Trichrome stains, with significant group differences (KW p-values < 0.05). Conclusion: Metformin showed a slightly stronger antifibrotic effect, reflected in greater normalization of lung weight and histopathological markers, though it was associated with weight loss .In contrast, Canagliflozin preserved body weight while also demonstrating strong anti-inflammatory and antioxidant properties. These results suggest that Canagliflozin could be promising candidates for the management of lung fibrosis. Metformin may be preferred for its robust antifibrotic effects, while Canagliflozin offers additional benefits in metabolic regulation and weight preservation. Keywords: Antifibrotic and Anti-inflammatory, Metformin and Canagliflozin , Lung Fibrosis Models