Tetracyclines were discovered as antibiotics in the 1950s and went on to save thousands of lives, with the only major side effect being phototoxicity. However, this side effect suggested that tetracyclines could act as dual-function light-activated antibiotics by specifically binding to bacterial cells and killing them only upon illumination. Moreover, the remaining tetracycline molecules could prevent bacterial regrowth after the illumination ceased, which is not the case with most antimicrobial photosensitizers. aPDI employing doxycycline (DOTC), demeclocycline (DMCT), and tetracycline (TET) excited with UVA or blue light killed up to six logs of Gram-negative E. coli and Gram-positive methicillin-resistant Staphylococcus aureus. Minocycline was not effective. aPDI could be potentiated by the addition of potassium iodide (KI). Azide quenched the formation of iodine, but not hydrogen peroxide. DMCT but not DOTC iodinated tyrosine in the presence of KI and light. A mouse model of a superficial wound infection caused by bioluminescent E. coli could be treated by topical application of DMCT and blue light. Bacterial regrowth did not occur after light owing to the continued antibiotic activity of the tetracycline. Since topical tetracyclines are already used clinically to treat superficial infections, additional blue light activation may be possible in these patients.