Drug-induced liver injuries often progress to acute liver failure (ALF) with a high mortality rate. Once ALF has commenced, therapy is minimal. Here, we report that the small bioactive compound SCM-198 (4-guanidino-n-butyl syringate) enables 100% survival of ALF mice induced by paracetamol (APAP) or thioacetamide (TAA) overdoes, even given therapeutically after the establishment of ALF. SCM-198 rapidly recovers liver functions within 6 hours. Using affinity purification and LC-MS, we identify that adiponectin receptor 2 (AdipoR2), but not AdipoR1, is a selective target of SCM-198 mediating the hepatoprotection function of SCM-198. AdipoR2 interacts with SCM-198 through the R335 residues, forming putative guanidine-arginine pairing, with a dissociation constant of 2.3 µM determined by MST and SPR. SCM-198-AdipoR2 does not signal through the AMPK or mTOR pathways, but by increasing the activity of a newly identified AdipoR2-CaM-CaMKII-NOS3 complex, which is pre-exited in liver cells. SCM-198-AdipoR2 binding causes Ca2+ influx and restores the phosphorylation level of CaMKII and NOS3, with the Y274 residue of AdipoR2 serving as a molecular switch for Ca2+ influx. This enables the rapid action of SCM-198 in regulating the levels of nitric oxide (NO) for liver protection in wild type, but not in Adipor2-/- or NOS3-/- mice. Moderately elevated NO attenuates inflammation, regulates lipid metabolism, and stimulates cell proliferation. SCM-198-activation of AdipoR2 also protects human ESC-derived liver organoids from oxidative stress, APAP, or TAA injuries. Together, these results demonstrate that selective targeting of the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 is a rapid-acting therapeutic strategy for ALF, both in mouse models and human organoid models, and provides an avenue for selective regulation of AdipoR2 signal transduction in organ regeneration and repair.