Geophysical processes of the pre-earthquake activities are difficult to be determined since less pre-seismic signal is observed directly. Crustal density changes derived from the periodical terrestrial gravimetry may provide meaningful deep information for the pre-earthquake cue. In this study, the crustal density changes following the 2016 M_S6.4 Menyuan earthquake are estimated using ground-based gravity-change data from 2011 to 2015 in the northeastern Tibetan Plateau. The results show that negative density changes dominate the region between the South Longshou Mountain fault and the Daban Mountain fault except the southeast of this region (the seismic region) during 2011–2012. Positive density changes appeared in the middle crust near the epicenter during 2012–2013 and in the upper and middle crust east of the epicenter approximately 1.5 years before the earthquake (2013–2014), and then negative density changes appeared under and northeast of the epicenter approximately four months before the earthquake (2014–2015). The state of the crustal materials near the seismic region changed from convergence to expansion, in turn, indicating that the characteristics of the deep seismogenic process was corresponding to Amos Nur’s 1974 dilatancy-fluid diffusion model.