An earthquake swarm in the Wakayama prefecture, Japan, is known as the most active and persistent swarm, with ~ 100,000 earthquakes occurring during the 2003–2020 period. However, no systematic studies have highlighted the source of this intriguing non-volcanic earthquake swarm to date. In this study, we systematically investigate the temporal and spatial evolution of the Wakayama earthquake swarm and estimate the seismic velocity structure around the Kii peninsula, where there are series of anomalous geophysical and geochemical signatures, such as high 3He/4He ratios, deep low-frequency earthquakes that occur far from active volcanoes, and hot springs with high salinity and solute concentrations. We reveal that seismicity associated with the Wakayama earthquake swarm occurs almost evenly in both time and space, and that the majority of the earthquakes occur along well-defined planes that dip to the west at 30–45º. Although the focal depths of the earthquakes in the swarm are 5–10 km shallower than those for the surrounding crustal earthquakes, b value (0.96) of the earthquake swarm is not distinct from the surrounding earthquakes. The seismic tomography results reveal the presence of an inclined low-velocity anomaly beneath the Wakayama swarm that is sandwiched by high-velocity, impermeable materials on both sides in the subduction direction. This unique tectonic setting controls a pathway that facilitates the upward migration of slab-derived fluids, with the high fluid concentration in this inclined low-velocity zone interpreted as a permeable zone. Therefore, we infer that the location of the Wakayama swarm is controlled by structural heterogeneities in the crust. This study further suggests that the anomalous geophysical and geochemical signatures observed across the Kii peninsula can be explained by the upward migration of the slab-derived fluids, with these varying signatures that are caused by the fluid migration pathways to the surface.