Ras is a node protein in the classic tumor signaling pathway known as RAS-RAF-MEK. Mutations in Ras are reported to occur in approximately 19% of human cancers. Among them, the G12D mutation is one of the most prevalent mutations found in Ras. In this study, we performed replica-exchange molecular dynamics (REMD) simulations on the KRas G12D mutant, revealing that its conformational space is remarkably different from that of wild-type KRas, particularly in State 1. Based on two specific conformations of the KRas G12D mutant, we screened an in-house molecular library. Two compounds, designated SS-3091 and SS-30125, were experimentally verified to have the strong inhibitory effects. MD simulations starting from the docked complexes revealed that SS-3091 and SS-30125 bind to the interaction interfaces of KRas and ARaf, destabilizing the ARaf·KRas complex. The anticancer activities of SS-3091 and SS-30125 have been validated against the KRas G12D, G12C, G12V, and G12S mutants in various cancer cells. All findings underscore the potential of SS-3091 and SS-30125 as very promising active pan-KRas inhibitors.