The 2021 Mw 7.4 Maduo earthquake ruptured the Jiangcuo fault, a secondary fault within the Bayan Har block, NE Tibetan Plateau, which attests that large earthquakes can occur on faults with very low slip rates. In this study, we use data from local seismic stations to explore the 3D velocity structure beneath the source region of the Maduo earthquake. Our results indicate that there is a distinct low-velocity anomaly in the mid-lower crust, and the thickness of this low-velocity zone decreases sharply to the east. The Maduo earthquake occurred in the transition zone between the high- and low-velocity regions. Based on our local velocity model and our knowledge of the regional crustal structures, we constructed numerical models to investigate the stress and strain energy distributions in our study area. As indicated by the stress concentration, strain energy accumulation, and low strain rate in the shallow upper crust around the source region, we conclude that the seismic velocity heterogeneity and the weak ductile mid-lower crust provide a unique tectonic environment that facilitated the nucleation of the Maduo earthquake. This study helps to understand the mechanisms of the Maduo earthquake, and more importantly reconciles the seeming contradiction between large earthquakes and low slip and strain rates. •The distinct low P- and S-wave velocity anomalies are observed beneath the source region, and the thickness of anomalies decreases eastward.•The Maduo earthquake is located in the transition zone between the high- and low-velocity regions.•The modeled stress and strain energy concentrated around the source region of the 2021 Mw 7.4 Maduo earthquake.•Our results provide a mechanism for large earthquakes occurring on faults with low slip and strain rates.