Background: Interstitial cystitis (IC) is a chronic bladder disorder character-ized by pelvic pain, urinary urgency, and frequent occurrence without infection. Animal models using chemical inducers are essential for studying IC pathophysiol-ogy; however, standardized comparative evaluations are scarce. Methods: This study compared three chemical-induced IC models: lipopolysaccharide (LPS), acetic acid (AA), and cyclophosphamide (CYP), in female C57BL/6 mice (n = 32, 8/group). Cystometric parameters including basal pressure, threshold pressure, peak pressure, intercontraction interval (ICI), and non-voiding contractions (NVCs) were measured. Bladder histology was assessed using hematoxylin and eosin staining. The expres-sion of caspase-9, NF-κB, and cytokeratin-20 (CK20) was analyzed using western blotting. Results: AA-treated mice exhibited the most severe urothelial disruption, with significantly elevated caspase-9 (3.1-fold) and NF-κB (2.8-fold) expression as well as reduced CK20 levels (p < 0.05). Functionally, the AA group showed a short-ened ICI (82.4 ± 10.1 s) and increased NVCs. LPS induced prolonged ICI (161.3 ± 8.9 s) with moderate inflammation, while CYP increased basal pressure (14.7 ± 1.6 cmH₂O) and NVCs, indicating detrusor overactivity. Conclusion: Among the tested models, acetic acid induction yielded the most consistent inflammatory, histological, and functional IC phenotypes, making it a robust model to study epithelial injury and acute bladder inflammation. These findings provide a standardized framework for selecting appropriate IC models for translational research.