Abstract: Objective To synthesize 2’,4’,6’-trihydroxychalcone derivatives and study their antidepressant activity and mechanism. Methods The 2’,4’,6’-trihydroxyacetophenone was used as the starting material;by hydroxyl protection,alodl condensation reaction and hydrolysis reactions,we get the target compounds 3a-3k,its structure was confirmed by IR,1HNMR and MS.The antidepressant activities of the target compounds were evaluated by using the forced swim test(FST) and tail suspension test(TST) in rats.The 5-HTP induced head-twitch and yohimbine-induced lethality tests were used to observe the impact of the synthesized compound 3h on the head-twitch and yohimbine-induced lethality in mice. Results The results showed that all six compounds significantly reduced the immobility times during the FST at a dose of 10 mg/kg,indicative of antidepressant activity.The compound 3h showed the most antidepressant activity.In addition,compound 3h showed antidepressant activity at three doses of 10 mg/kg,20 mg/kg and 40 mg/kg,significantly reduced immobility times in FST and TST in mice.It was found to be the most antidepressant activity at 20 mg/kg.The compound 3h increased the head-twitch and had not raised the mortality of mice. Conclusion Six compounds showed significantly the antidepressant activity.The mechanism may be related to the system of 5-HT in central nervous system.