Increasing concentrations of anthropogenic antibiotics and their metabolites in aqueous environments has caused growing concerns over the proliferation of antibiotic resistance and potential adverse impacts to agro-environmental quality and human health. Photocatalysis using novel engineered nanomaterials such as ZnO nanowires may be promising for removing antibiotics from waters. However, much remains to be learned about efficiency and mechanism for photocatalytic degradation of antibiotics by ZnO nanowires. This study systematically investigated photodegradation of cephalexin using ZnO nanowires under simulated sunlight. The degradation efficiency of cephalexin was substantially increased in the presence of ZnO nanowires especially at circumneutral and alkaline condition (solution pH of 7.2-9.2). The photodegradation followed the first-order kinetics with degradation rate constants (k) ranging between 1.19 × 10-1 and 2.52 × 10-1 min-1 at 20-80 mg L-1 ZnO nanowires. Radical trapping experiments demonstrated that hydroxyl radicals (OH) and superoxide radicals (O2-) predominantly contributed to the removal of cephalexin. With the addition of HCO3- (1-5 mM) or Suwannee River natural organic matter (SRNOM, 2-10 mg L-1), the k values were substantially decreased by a factor of 1.8-70 to 1.69 × 10-3-6.67 × 10-2 min-1, probably due to screening effect of HCO3- or SRNOM sorbed on ZnO nanowires and scavenging of free radicals by free HCO3- or SRNOM in solution. Combining product identification by mass spectrometry and molecular computation, cephalexin photodegradation pathways were identified, including hydroxylation, demethylation, decarboxylation, and dealkylation. Overall, the novel ZnO nanowires have the potential to be used for removing antibiotics from contaminated waters.