From the consideration of the regional power grid as a whole, this paper defines the main protection and backup protection of the centralized network of regional power grid protection, and proposes the hierarchical differential protection method. Double-linked list structure is used to express the grid topology according to characteristics of the regional grid topology, and the identification of topology is analyzed with specific examples. This paper also studies fault handling process of the grid centralized protection and proposes the principle of scheduling voltage line selection firstly and then calculating differential tripping after the start of the current-contracting. A regional power grid simulation system including four 220 kV substations is established using RTDS. Dynamic simulation test results show that except for possessing the traditional main protection functions, the reserve differential protection of centralized differential protection of the regional power grid has the features of good selectivity, high sensitivity, and fast action compared with traditional remote backup protection.