Degradation of naproxen (NAP) by persulfate (PS) activated with zero-valent iron (ZVI) was investigated in our study. The NAP in aqueous solution was degraded effectively by the ZVI/PS system and the degradation exhibited a pseudo-first-order kinetics pattern. Both sulfate radical (SO4•−) and hydroxyl radical (HO•) participate in the NAP degradation. The second-order rate constants for NAP reacting with SO4•− and HO• were (5.64 ± 0.73) × 109 M−1 s−1 and (9.05 ± 0.51) × 109 M−1 s−1, respectively. Influence of key parameters (initial pH, PS dosage, ZVI dosage, and NAP dosage) on NAP degradation were evaluated systematically. Based on the detected intermediates, the pathways of NAP degradation in ZVI/PS system was proposed. It was found that the presence of ammonia accelerated the corrosion of ZVI and thus promoted the release of Fe2+, which induced the increased generation of sulfate radicals from PS and promoted the degradation of NAP. Compared to its counterpart without ammonia, the degradation rates of NAP by ZVI/PS were increased to 3.6–17.5 folds and 1.2–2.2 folds under pH 7 and pH 9, respectively.