The adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a metabolic stress sensing kinase that is activated by depletion in cellular adenylate charge, triggering AMPK phosphorylation on the α-subunit activation loop Thr172 by upstream kinases LKB1 or CaMKKβ.  Activated AMPK redirects cellular metabolism to restore cellular energy balance by phosphorylating key enzymes in all branches of metabolism.  Many diseases including obesity, Type 2 diabetes, cardiovascular disease and cancer have metabolic dimensions that have encouraged efforts to develop direct activating drugs for AMPK.  A number of direct AMPK activating drugs have been identified including A-769662 but their mechanism of action has been poorly understood.  The β-subunit carbohydrate-binding module is required for A-769662 activation and mutation of the β-subunit autophosphorylated residue Ser108 to Ala abolishes activation.  Here we show that A-769662 in the presence of AMP can activate AMPK harbouring both α-T172A and β-S108A mutations approximately 1000-fold, whereas either ligand alone does not activate.  Consequently A-769662 and AMP together are sufficient to activate dephosphorylated, naive AMPK entirely allosterically and independently of upstream kinase signalling and autophosphorylation cycles.  These findings provide a simple model of AMPK activation by drugs and a means to assess their mechanisms of action.