A range of hydrophobic first-, second-, and third-generation manganese porphyrins (MnPs) was investigated as cytochrome P450 models for degradation of the antibiotic ciprofloxacin (CIP). The experiments were carried out under mild conditions; oxidants such as iodosylbenzene (PhIO), H2O2, and meta-chloroperbenzoic acid were employed. The PhIO system yielded the best results: CIP degradation ranged between 56% and 76%. CIP degradation was not directly related to MnP generation. The second-generation MnP afforded the best result with the advantage that it required less preparation effort as compared to the third-generation MnP. Some new degradation products in MnP-mediated ciprofloxacin degradation were proposed, and the products of the reaction are not cytotoxic under the conditions evaluated.