This study investigated the off-target effects of SGLT2 inhibitors and metformin on intestinal smooth muscle contractility, with particular emphasis on the role of AMP-activated protein kinase (AMPK). Ex vivo organ bath experiments were used to evaluate the effects of dapagliflozin and metformin on spontaneous and carbachol-induced contractions, while additional analyses examined the potential involvement of SGLT1/2 inhibition, the Na⁺/H⁺ exchanger (NHE), and AMPK signaling. Dapagliflozin significantly reduced intestinal contractility, and AMPK inhibition partially reversed this effect, suggesting that AMPK contributes to the observed response. However, the incomplete reversal indicates that additional mechanisms may also be involved, and biochemical confirmation of AMPK activation was not achieved within the study timeframe. These findings provide mechanistic insight into reduced intestinal contractility and suggest that AMPK activation contributes to the inhibitory effects of SGLT2 inhibition on intestinal motility. Understanding this relationship may help explain clinically observed gastrointestinal side effects and support strategies to improve patient adherence.