The American cockroach, Periplaneta americana (L.), is a notorious urban pest. It has developed insecticidal resistance to commonly used insecticides. Cantharidin (CTD) is a defensive toxin derived from blister beetles. It has been verified to have insecticidal toxicity in a range of pests. In this study, we determined the ingestion toxicity of CTD and norcantharidin (NCTD) to P. americana to test whether they had the potential to be effective against P. americana. Bioassays revealed that CTD produces toxicity against P. americana. The median lethal concentration (LC50) value of CTD was 50.92 μg/mL, while NCTD displayed nearly no toxicity against P. americana. The inhibition assays of serine/threonine protein phosphatases (PSPs) in P. americana indicated that CTD and NCTD could inhibit PSPs. The value of the half maximal inhibitory concentration (IC50) of CTD was 7.21 ± 0.94 μM, whereas that of NCTD was higher, at 31.65 ± 3.87 μM. Furthermore, the inhibition effect of CTD on the serine/threonine protein phosphatase type 5 of P. americana (PaPP5) was superior to that of NCTD. Specifically, the IC50 of CTD reached 0.39 ± 0.04 μM, while the IC50 of NCTD was 1.87 ± 0.23 μM. This study paves the way for insect-derived agents (CTD) to be applied toward controlling P. americana and contributes to the development of novel insecticides based on PP5 as a target.