The wide occurrence of antibiotics in groundwater raised great scientific interest as well as public awareness in recent years due to their potential ability to spread antibiotic resistant gene and pose risk to humans. The present study investigated the ferrous ion (Fe(II)) activated decomposition of persulfate (S2O8(2-)), as a potential in situ chemical oxidation (ISCO) approach, for remediation of groundwater contaminated by antibiotics. Fe(II)-persulfate mediated ciprofloxacin (CIP) degradation was found to be more efficient than sulfamethoxazole (SMX) at near neutral pH (pH6.0), probably due to the higher electric density in CIP molecule and its ability to form complex with Fe(II) as a ligand. Hydroxyl (HO) and sulfate radical (SO4(-)) were determined to be responsible for the degradation of CIP and SMX in Fe(II)-persulfate system by molecular probes. No enhancement in the degradation of CIP was observed when citrate (CA), ethylenediaminetetraacetate (EDTA) and (S,S)-ethylenediamine-N,N'-disuccinate (EDDS) were used as Fe(II) chelating agents in Fe(II)-persulfate system. For SMX, CA and EDTA accelerated the degradation by Fe(II)-persulfate. Degradation of antibiotics in river water matrix was nearly the same as that in Milli-Q water, implying the possibility of using Fe(II)-persulfate for antibiotics depletion under environmentally relevant condition. A comparison of the degradation efficiency of SMX with other sulfonamides and sulfanilic acid indicated that the heterocyclic ring has a large impact on the degradation of sulfonamides. Transformation products of CIP and SMX by Fe(II)-persulfate were analyzed by solid phase extraction-liquid chromatography-mass spectrometry (SPE-LC-MS) technique. Based on the intermediate products, Fe(II)-persulfate mediated CIP degradation pathways were tentatively proposed.