NRF2 (Nuclear factor E2 p45-related factor 2) is a stress responsive transcription factor lending cells resilience against oxidative, xenobiotic, and also nutrient or proteotoxic insults. AMPK (AMP-activated kinase), considered as prime regulator of cellular energy homeostasis, not only tunes metabolism to provide the cell at any time with sufficient ATP or building blocks, but also controls redox balance and inflammation. Due to observed overlapping cellular responses upon AMPK or NRF2 activation and common stressors impinging on both AMPK and NRF2 signaling, it is plausible to assume that AMPK and NRF2 signaling may interdepend and cooperate to readjust cellular homeostasis. After a short introduction of the two players this narrative review paints the current picture on how AMPK and NRF2 signaling might interact on the molecular level, and highlights their possible crosstalk in selected examples of pathophysiology or bioactivity of drugs and phytochemicals.