The present invention relates to a centralized and networked protection system and method of regional distribution network, and belongs to the field of electrical system automation and relay protection. The protection system includes at least two centralized protection devices, an intelligent terminal and a communication network module, the centralized protection devices being communication with the intelligent terminal via the communication network module, the intelligent terminal being configured along with switching devices to distribute in each line section, for sampling data, backup protection and executing of tripping and closing commands, the centralized protection devices configured in the monitoring center of the regional distribution network, for generating differential protection elements based on the information sampled by the intelligent terminal and the topologic structure of the regional distribution network; and for determining the region where fault occurs and sending tripping and closing control commands.