The antidepressant-like effects of phloroglucinol and seven synthetic related derivatives were investigated using the tail suspension test (TST) in mice. Compounds 2-methyl-1-[2,4,6-trihydroxy-3-(2-methylpropanoyl)phenyl] propan-1-one (5), 1-(2,4,6-trihydroxyphenyl)ethan-1-one (6), 1-(3-acetyl-2,4,6-trihydroxyphenyl)ethan-1-one (7), 2-methyl-1-[2,4,6-trihydroxy-3-(2-methylpropanoyl)-5-{[2,4,6-trihydroxy-3,5-bis(2-methylpropanoyl)phenyl]methyl} phenyl] propan-1-one (9) and 1-{3-acetyl-5-[(3,5-diacetyl-2,4,6-trihydroxyphenyl)methyl]-2,4,6-trihydroxyphenyl}ethan-1-one (10), containing acyl groups, decreased the immobile behavior of mice treated orally with equimolar doses of imipramine 20 mg/kg, with no alterations in locomotor activity as assessed by the open-field test. These results suggest that these phloroglucinol derivatives could represent a new molecular model in the search for antidepressant drugs.