Introduction: Relevant factors underlying major depressive disorder (MDD) are childhood stress and a lack of social support, which are mimicked in animal models by maternal deprivation (MD) and social isolation (SI). The objective was to evaluate depressive-like behaviors in rats subjected to MD and SI and in the female offspring, and to assess the treatment with Centella asiatica and madecassic acid. Methods: This study assessed the effects of MD and SI stress on young adult Wistar male and female rats from the first-generation and non-stressed offspring of stressed mothers. Forced swimming and open-field tests were conducted in 92-94 days, and the possible therapeutic effect of Centella asiatica (30 mg/kg) hydroalcoholic extract and madecassic acid (10 mg/kg) administered by gavage for fourteen days was investigated. Data were analyzed using ANOVA and Tukey's post hoc test (p < 0.05). Results: In the forced swimming test, immobility time was higher in the stress + saline group compared to the stress-free control group, and all treatments reversed this depressive-like behavior in the first phase. In the second phase, immobility time was higher in the offspring + saline group compared to the control group, and treatment with Centella asiatica in males and Centella asiatica and madecassic acid in females reversed this behavior. Conclusions: Stress in the first generation causes depressive-like behavior in rats, which Centella asiatica and madecassic acid can counteract. Mothers' childhood stress can have intergenerational effects on their children, and treatments with Centella asiatica and madecassic acid reduced depressive-like behaviors in stressed mothers and their offspring.