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Background and Purpose: Kaempferol‐3‐O‐sophoroside (PCS‐1) is the main component in Crocus sativus (Saffron), a herb with mood‐enhancing properties. AMP‐activated protein kinase (AMPK) is a potential therapeutic target for depression. This study explores the antidepressive‐like properties of PCS‐1 and its AMPK activation to confirm AMPK as a target for antidepression. Experimental Approach: Corticosterone (CORT)‐induced PC12 cell injury served as an in vitro model to evaluate the neuroprotective effect of PCS‐1. Neuro‐2a cells and primary neurons were utilized to evaluate the synaptogenesis role of PCS‐1. CORT‐induced mouse depression model and chronic unpredictable mild stress (CUMS) model were used to assess the antidepressive‐like properties of PCS‐1 through behavioural tests, magnetic resonance imaging, and biochemical index measurements. Western blot and immunofluorescence assays were used to study the mechanisms of PCS‐1. Cellular thermal shift assay was used to confirm the binding target. Key Results: PCS‐1 (12.5–50 μM) ameliorated CORT‐induced PC12 cell damage, oxidative stress and inflammation. PCS‐1 alone promoted an increase in synapses in Neuro‐2a cells and primary neurons. Oral administration of PCS‐1 (10 and 20 mg·kg−1) ameliorated weight loss, dyskinesia, and hippocampal volume reduction induced by CORT and CUMS. PCS‐1 bound to AMPK to improve the expression of brain‐derived neurotrophic factor (BDNF) and induce autophagy. Conclusion and Implications: PCS‐1 binds to AMPK to promote BDNF production and autophagy enhancement, ultimately achieving antidepressant effects. This study provides support for the clinical application of saffron petals and provides further evidence for AMPK as a potential target for antidepression. [ABSTRACT FROM AUTHOR]