Complexation of tetracyclines (TCs) with dissolved Mn(II) and Cu(II) ions were found to significantly enhance the transformation of these antibiotics in the presence of oxygen at pH 8-9.5 and pH 4-6, respectively. In the TC-Mn(II)-O2 system, oxidation of the TC-complexed Mn(II) to Mn(III) by oxygen occurs, followed by oxidation of TC by Mn(III) to regenerate Mn(II). In the TC-Cu(II)-O2 system, Cu(II) oxidizes TC within the complex and the yielded Cu(I) is reoxidized by the present oxygen. Opposite reactivity trends were observed with the two metals: OTC (oxytetracycline) > TTC (tetracycline) >> iso-CTC (iso-chlorotetracycline) for the Mn(II)-mediated reaction, whereas CTC > TTC > OTC > epimers for the Cu(II)-mediated reaction. The reactivity results and examination of TC-metal ion complexation and transformation products suggest that the BCD-ring and A-ring of TC are crucial to interact with Mn(II) and Cu(II), respectively. This study highlights that the fate of TCs in aquatic environments may differ significantly by their strong interactions with different metal species present in the systems.