Heterodera glycines, the soybean cyst nematode, penetrates soybean roots and migrates to the vascular cylinder where it forms a feeding site called the syncytium. MiRNA396 (miR396) targets growth-regulating factor (GRF) genes, and the miR396–GRF1/3 module is a master regulator of syncytium development in model cyst nematode H. schachtii infection of Arabidopsis. Here, we investigated whether this regulatory system operates similarly in soybean roots and is likewise important for H. glycines infection. We found that a network involving nine MIR396 and 23 GRF genes is important for normal development of soybean roots and that GRF function is specified in the root apical meristem by miR396. All MIR396 genes are down-regulated in the syncytium during its formation phase while, specifically, 11 different GRF genes are up-regulated. The switch to the syncytium maintenance phase coincides with up-regulation of MIR396 and down-regulation of the 11 GRF genes specifically via post-transcriptional regulation by miR396. Furthermore, interference with the miR396–GRF6/8–13/15–17/19 regulatory network, through either overexpression or knockdown experiments, does not affect the number of H. glycines juveniles that enter the vascular cylinder to initiate syncytia, but specifically inhibits efficient H. glycines development to adult females. Therefore, homeostasis in the miR396–GRF6/8–13/15–17/19 regulatory network is essential for productive H. glycines infections.