When the power system substation or its transmission line occurs system fault after substation’s secondary DC power has lost, the stability of the system will be reduced because the protection device can’t isolate the fault quickly. In order to solve this problem, a protection system of substation’s secondary DC power loss based on regional power grid information is presented, which is oriented to substation. The regional master-sub-substation control system’s concept and its construct mode, the judgment of substation’s secondary DC power loss, as well as the whole program of secondary DC power loss protection, are introduced in detail. The confirmatory test based on the RTDS simulation indicates that the presented judgment of substation’s secondary DC power loss and whole program have superior performance, which can correctly judge substation’s secondary DC power loss state and quickly isolate the fault in the area.