Hypertension‐induced cardiac hypertrophy and apoptosis are major characteristics of early‐stage heart failure (HF). Inhibition of extracellular signal‐regulated kinases (ERK) efficaciously suppressed angiotensin II (ANG II)‐induced cardiomyocyte hypertrophy and apoptosis by blocking insulin‐like growth factor II receptor (IGF‐IIR) signaling. However, the detailed mechanism by which ANG II induces ERK‐mediated IGF‐IIR signaling remains elusive. Here, we found that ANG II activated ERK to upregulate IGF‐IIR expression via the angiotensin II type I receptor (AT1R). ERK activation subsequently phosphorylates HSF1 at serine 307, leading to a secondary phosphorylation by glycogen synthase kinase III (GSK3) at serine 303. Moreover, we found that ANG II mediated ERK/GSK3‐induced IGF‐IIR protein stability by downregulating the E3 ubiquitin ligase of IGF‐IIR RING finger protein CXXVI (RNF126). The expression of RNF126 decreased following ANG II‐induced HSF1S303 phosphorylation, resulting in IGF‐IIR protein stability and increased cardiomyocyte injury. Inhibition of GSK3 significantly alleviated ANG II‐induced cardiac hypertrophy in vivo and in vitro. Taken together, these results suggest that HSF1 phosphorylation stabilizes IGF‐IIR protein stability by downregulating RNF126 during cardiac hypertrophy. ANG II activates ERK/GSK3 to phosphorylate HSF1, resulting in RNF126 degradation, which stabilizes IGF‐IIR protein expression and eventually results in cardiac hypertrophy. HSF1 could be a valuable therapeutic target for cardiac diseases among hypertensive patients. This article is protected by copyright. All rights reserved