Uncaria rhynchophylla (UR) is a traditional Chinese herb widely used for hyperpyrexia, epilepsy, preeclampsia, and hypertension. In this paper, the potential anti-pseudo-allergic components in UR were explored. Six alkaloids in UR possessed good retention properties on an established MRGPRX2/CMC model. Among them, isorhynchophylline (Isorhy) and corynoxeine (Cor) could inhibit the pseudo-allergic reaction induced by C48/80 both in vivo and in vitro. Therefore, this study provides evidence for the anti-pseudo-allergic effect of UR and for development of the biological activity of this genus.