A recent investigation has demonstrated that peroxymonosulfate (PMS), a peroxide commonly applied as a radical precursor during advanced oxidation processes (AOPs), can degrade organic contaminants without the involvement of radicals. However, little is known about this non-radical reaction mechanism. In this study, the reactivity of PMS with several nitrogenous compounds was investigated. Fluoroquinolone antibiotics (except for flumequine) were rapidly degraded by direct PMS oxidation, followed by aliphatic amines (e.g., metoprolol and venlafaxine) and nitrogenous heterocyclic compounds (e.g., adenine and caffeine) at pH 8. The degradation rate of fluoroquinolones followed a second-order kinetic and was highly pH and structure-dependent. Unlike the radical-based AOPs, the direct degradation of contaminants by PMS was less influenced by the scavenging effect of the water matrix. High-Resolution Mass Spectrometry (HRMS) analysis demonstrated that the piperazine ring of fluoroquinolones was the main reaction site. Results showed that the direct electron-transfer from nitrogenous moieties (piperazine ring) to PMS can produce amide and aldehyde compounds. An amide-containing transformation product of ciprofloxacin (m/z 320), showing the highest signal intensity on HRMS, was previously recorded during ozonation. Moreover, the hydroxylamine analogue of ciprofloxacin and enrofloxacin N-oxide were tentatively identified, and the formation of the latter was not impacted by the dissolved oxygen in water. These results suggested that PMS also reacts with nitrogenous compounds via oxygen transfer pathway. Agar disk-diffusion tests indicated that PMS treatment efficiently removed the antibacterial activity of ciprofloxacin with the complete degradation of parent antibiotic, except for the transformation products in an earlier stage, which might still exert antibacterial potency.