Background and aims: Lemon balm (Melissa officinalis) in many countries is used as a nerve calming, spasmolytic, and antibacterial agent. Anyway, more investigations are needed to determine toxic effects of this plant. In this study, we investigated the effects of lemon balm hydroalcoholic extract on some biochemical enzymes and tissue changes (in kidney and liver) in mice.Methods: In this experimental study, 21 male mice were randomly divided into three groups of seven mice each. Group I was treated with normal saline as control and experimental groups II and III were treated with hydroalcoholic extract of lemon balm daily for two weeks intraperitoneally in doses of 0.450 and 1.350 g/kg, respectively. At the end of the experimental period (15 days), blood samples were obtained from the heart and centrifuged, and then the sera were evaluated to determine the concentrations of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine, and urea using autoanalyzer and commercial kits. In addition, the liver and kidney tissues were removed and examined after fixation in formalin buffer 10% and hematoxyline-eosin staining. The data were analyzed at a significance level of p<0.05 by one-way ANOVA, Tukey’s post hoc test, and Kruskal-Wallis.Results: Lemon balm caused a significant reduction in alanine aminotransferase and alkaline phosphatase levels compared to the control group. Also, it showed a dose-dependent effect.Furthermore, lemon balm extract had no effect on the amount of urea and creatinine compared to the control group. Histopathological changes of the liver and kidney in the groups that received different doses of the extract showed mild, moderate, and severe tissue injuries.Conclusion: The biochemical analysis in this study indicates that the extract of lemon balm causes liver tissue damage in mice; therefore, plant’s consumption in high doses should be avoided.