Introduction: Ferulic acid, a phenolic phytochemical with neuroprotective, anti-inflammatory, and antioxidant properties, has shown promising antidepressant-like effects in behavioral studies; however, its mechanism(s) of action have not been fully understood. Based on the contribution of nerve growth factor (NGF) and endocannabinoid signaling (eCBs) to the emotional or antidepressant activity and their interaction, we aimed to evaluate whether ferulic acid affects NGF or eCB contents in the brain regions involved in the modulation of emotions. Methods: Following single and four-week once-daily intraperitoneal injections of ferulic acid (50, 100, 130 and 150 mg/kg), amitriptyline (2.5, 5, 8 and 10 mg/kg) or lorazepam (2, 5, 8 and 10 mg/kg) into male Wistar rats, NGF and eCB levels were quantified by Bio-Rad protein assay and isotope-dilution liquid chromatography/mass spectrometry. In the case of significant alteration of brain NGF or eCB content, the effects of pre-treatment with cannabinoid CB1 or CB2 receptor antagonist (AM251 or SR144528) were investigated. Results: Four-week treatment with the highest doses of ferulic acid or amitriptyline led to a significant and sustained enhancement of eCB and NGF contents in brain region-specific fashion. Neither acute nor four-week treatment with lorazepam affected NGF or eCB levels. Pre-treatment with AM251 (3 mg/kg), but not SR144528, prevented the elevation of NGF levels. AM251 showed no effect by itself. Conclusion: Ferulic acid similar to the conventional antidepressant, amitriptyline, affects brain eCB and NGF signaling. CB1 receptors mediate the production of brain NGF.