The aim of this study was to evaluate the antidepressant-like effect of the acute administration of blueberry extract in mice. In addition, the digestion behavior of individual phenolic compounds using an in vitro digestion model was also investigated and the main bioaccessible compounds were determined. During digestion, important changes were observed in the polyphenols concentrations and antioxidant capacity upon the passage through the gastric and enteric phases. Bioactive compounds such as chlorogenic and ferulic acids, catechin, epicatechin, quercetin and malvidin were highly bioaccessible from the blueberry. The in vivo experiment was carried out with males Swiss mices; for the evaluation of the minimum effective dose of the extract, mices were treated with different concentrations (200, 300 and 400 mg/kg) of the blueberry extract. The animals were submitted to behavior tests and the minimum effective dose of the blueberry extract was established as 300 mg/kg. The results indicated a decrease in the immobility time of mice in the tail suspension test without any effect on the locomotor activity in the open field test when treated with the minimum effective dose. This dose was then chosen to carried out the tests of hepatotoxicity and results showed no evidences of toxic effects of blueberry extract. The acute administration of the blueberry extract also led to a significant decrease Thiobarbituric Acid Reactive Substances (TBARS) in mices hippocampus. The results observed suggest that the neuroprotective and antidepressant-like effects might be related to the phytochemical composition of the blueberry, particularly due to the high flavonols and anthocyanins concentrations.