The 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) flame retardants (DOPO-FRs) have attracted more and more attention in the flame-retardant industry due to their high efficiency, environmental protection, and good molecular design. During the flame-retardant process, the breakage of P-C bonds is very important to the flame-retardant effect. Through the comparison of different density functional theories (DFTs) on P-C BDEs, it was found that MN12-L has the highest calculation accuracy, and the root-mean-square error is the smallest with 1.85 kcal/mol. Therefore, MN12-L was selected to investigate P-C BDEs of different DOPO-FRs including thiophen-amine, benzo[d]thiazol-amine, triazol-amine, and aniline DOPO-FRs. By comparing the theoretical calculation of BDE with the experimental parameters of high limiting oxygen index (LOI) and vertical combustion test (UL-94 test), it was found that the P-C BDEs have a certain correlation with the flame-retardant effect. Finally, based on P-C BDEs, substituent effects, and effective flame-retardant fragments, a series of new DOPO-FRs were designed. The results showed that when only one DOPO fragment was contained, the effective fragments of flame retardants were ranked as furan > thiophene > triazole > imidazole. When bis-DOPO fragment was contained, the flame-retardant effect of diamino-triazole fragments was better than that of benzyldimethylamine fragments. In addition, when the substituents on the effective fragment have two EDGs, the flame-retardant effect is superimposed, which makes the flame-retardant performance more excellent.