In this study, a highly active electro-Fenton catalyst, spongy zero-valent iron (ZVI), has been developed at first via in-situ synthesis of ZVI nanoparticles (NPs) on an electrospun three-dimensional (3D) nanofiber network. The spongy ZVI effectively overcame the defects of easy aggregation of ZVI NPs and ferric sludge accumulation during the electro-catalytic process. Then, a three-dimensional electro-Fenton (3D-EF) system using the as-fabricated spongy ZVI as particle catalytic electrodes was designed, which presented a significant synergistic effect of adsorption and electro-catalytic oxidation on the enhanced removal of a widely used antibiotic, sulfathiazole (STZ) from water. Adsorption experiments demonstrated that the spongy ZVI had a relative high adsorption affinity towards STZ with about 50% of the total removal within 240 min, and the adsorption equilibrium was reached in 570 min. Hydroxyl radical (^.OH) was produced in the 3D-EF system with spongy ZVI catalyst, and almost 100% STZ was removed within 5 min. Reactive oxygen species analysis verified that OH was mainly responsible for the STZ degradation. Based on intermediates identified by a liquid chromatography-tandem mass spectrometry (LC–MS/MS), three pathways for the electro-Fenton oxidative degradation of STZ were proposed.