Aim: In addition to functioning as an energy sensor switch, AMPK plays a key role in the maintenance of cardiovascular homeostasis. However, obesity disrupts AMPK signaling, contributing to endothelial dysfunction and cardiovascular disease. This study aimed to elucidate if a short‐term dietary intervention consisting in replacing the high‐fat diet with a standard diet for 2 weeks could reverse obesity‐induced endothelial dysfunction via AMPK‐CREB activation. Methods: For this, 5‐week‐old male C57BL6J mice were fed a standard (Chow) or a high‐fat (HF) diet for 8 weeks. The HF diet was replaced by the chow diet for the last 2 weeks in half of HF mice, generating 3 groups: Chow, HF and HF‐Chow. Vascular reactivity and western‐blot assays were performed in the thoracic aorta. Results: Returning to a chow diet significantly reduced body weight and glucose intolerance. Relaxant responses to acetylcholine and the AMPK activator (AICAR) were significantly impaired in HF mice but improved in HF‐Chow mice. The protein levels of AMPKα, p‐CREB and antioxidant systems (heme oxygenase‐1 (HO‐1) and catalase) were significantly reduced in HF but normalized in HF‐Chow mice. Conclusion: Improving dietary intake by replacing a HF diet with a standard diet improves AMPK‐mediated responses due to the upregulation of the AMPK/CREB/HO‐1 signaling pathway. [ABSTRACT FROM AUTHOR]