The Tancheng-Lujiang Fault Zone (simplified as the Tanlu Fault Zone) is the biggest in east China. In 1668, an M8 earthquake occurred along this fault zone in Tancheng, Shandong Province, China. Seismologists are focusing on the most likely location of the next major earthquake along this fault, particularly in the areas near Shandong and Jiangsu provinces. The multiphase travel time inversion (MUTI) algorithm was developed to invert the three-dimensional crust velocity structure of the Shandong-Jiangsu segment of the Tanu Fault Zone and its adjacent area (30°~37° N, 113°~122° E). The crust can be divided into three layers, the upper (10~15 km thick), the middle (10~15 km thick) and the lower (10~12 km thick). The segmentation of the shallow velocity structure is consistent with that of fault activity, and indicates that the area from Xinyi to Sihong comprises the active fault block section. There is a low velocity layer at a depth of 20~25 km in the Tanlu Fault Zone from Linshu to Dingyuan and its eastern area. A low velocity layer can also be found in the middle crust of the source region of the 1668 Tancheng earthquake. In this study, we present the variation of Moho depths in Suqian, Siyang, Shuyang, and Tancheng. The Wuxi-Suqian fault, the Hongze-Goudun fault, and the Jiashan-Xiangshui fault all intersect with the Tanlu Fault Zone, and the intersection area of these faults may be dangerous. By comparing the depth velocity structure features of the Jiangsu segment along the Tanlu fault zone with the source area of the 1668 Tancheng M8 earthquake, combined with data regarding seismic activity, the active fault block, the low velocity layer in the middle crust, the depth variations of the Moho, and the fault intersections, the area of next large earthquake can be estimated for the Jiangsu segment of the Tanlu fault zone. The most likely position is 33.4°~34.1° N and 118.2°~118.8° E, in Suqian, Shuyang, Siyang and Sihong in particular. The estimated maximum magnitude is 8.