An-Gong-Niu-Huang Wan (AGNH) is a famous traditional Chinese medicine prescription that contains cinnabar (HgS) and realgar (As2S2); the clinical practice of AGNH is hindered because both mercury and arsenic are hepatorenal toxic metalloids. It is noted that the cinnabar and realgar in AGNH are not used alone, but rather combined with different kinds of medicinal herbs as a formula to use. In this study, we evaluated the hepatorenal protective effects of the medicinal herbs in AGNH after co-exposure to cinnabar and realgar for 4 weeks in mice. The combination of the herbs in AGNH alleviated cinnabar and realgar-induced histopathological alterations and oxidative stress in the liver and kidneys. Furthermore, in cinnabar and realgar-treated mice, the increased expression levels of inducible enzymes (COX-2 and iNOS) and proinflammatory mediators (IL-1 beta, TNF-alpha, PGE2 and NO) in the liver and kidneys were consistently down-regulated when medicinal herbs were combined as a formula. We also found that the herbs could reduce the inflammatory response by the inactivation of the MAPK and PI3K/Akt signaling pathway and the resulting blockade of NF-kappa B activation. Overall, our data indicates that the herbal medicines in AGNH attenuate cinnabar and realgar-induced hepatorenal toxicity by improving antioxidant competence and suppressing inflammatory injury.