Through transcriptional control of the powerful heat-shock or, proteotoxic stress, response (HSR/PSR), heat shock factor 1 (HSF1) preserves proteomic stability. Our studies reveal that HSF1, a physiological substrate for AMP-activated protein kinase (AMPK), suppresses this central metabolic sensor directly. By physically evoking conformational switching of AMPK, HSF1 blocks AMP binding to the γ subunits non-competitively, enhances the PP2A-mediated de-phosphorylation and impedes the LKB1-mediated phosphorylation of Thr172, as well as allosterically hinders ATP binding to the α subunits. These manifold regulations empower HSF1 to constrain AMPK activation in response to diverse cues, thereby sustaining cellular lipid content, serum lipid levels, liver and whole-body fat mass, as well as global protein cholesteroylation. In vivo, HSF1 antagonizes AMPK to drive the lipogenic phenotype and growth of melanomas, independently of its intrinsic transcriptional action. Thus, the physical AMPK-HSF1 interaction epitomizes an intriguing reciprocal kinase-substrate regulation whereby lipid metabolism and proteomic stability intertwine.