Zero-valent iron (Fe0), as an alternative iron source, was evaluated to activate persulfate (PS) to degrade acetaminophen (APAP), a representative pharmaceutically active compound in water. Effects of key factors in the so-called Fe0/PS process, including Fe0 dosage, initial pH, temperatures and chelating agents, were studied. Under all the conditions tested, the APAP degradation followed a pseudo-first-order kinetics pattern. The degradation efficiency of APAP was highest when the Fe0 to PS molar ratio increased to 1:1, and the degradation rate constant and removal were 23.19 × 10−3 min−1 and 93.19 %, respectively. Comparing with Fe2+, Fe0 served as an alternative iron source that can gradually release Fe2+ into water, thereby consistently activating PS to produce sulfate radicals. The Fe0/PS system was effective in a broader pH range from 3 to 8.5. Heat could facilitate production of sulfate radicals and enhance the APAP degradation in the Fe0/PS system. High reaction temperature also improved the Fe2+/PS oxidation of APAP. Finally, sodium citrate (a chelating agent) at an appropriate concentration could improve the APAP degradation rate in the Fe2+/PS and Fe0/PS system. The optimal molar ratio of Fe0 to citrate depended on solution pH. Our results demonstrated that Fe0 was an alternative iron source to activate PS to degrade APAP in water.