Introduction: Major depressive disorder (MDD) is a disorder strongly linked to childhood stress, amplified by a lack of social support later in life. Rodent models like maternal deprivation (MD) and social isolation (SI) mimic these traumas, highlighting how early-life stress can alter the hypothalamic–pituitary–adrenal (HPA) axis and be transmitted to offspring. Objective: The objective of this study is to evaluate depressive-like behaviors and HPA axis protein in rats subjected to MD and SI and in the stressed female offspring, as well as the therapeutic potential of Centella asiatica and its active compound, madecassic acid. Methods: The animals were male and female Wistar rats. MD consisted of depriving the pups three hours per day for ten days. SI consisted of keeping the animals in individual cages, starting at 50 days of age. Forced swimming and gene expression of the HPA axis proteins NR3C1 and FKBP5 in the Nucleus Accumbens (NAc) were evaluated in both animals that suffered stress and in offspring of mothers who experienced stress (second-generation). After 30 days of IS, the hydroalcoholic extract of Centella asiatica (30 mg/kg) and madecassic acid (10 mg/kg) were administered for fourteen days. Results: Stress from PM and IS resulted in depressive-like behavior in adulthood of the first-generation and in offspring (second-generation) from stressed mothers. Treatments with Centella asiática and madecassic acid reduced depressive-like behavior. These compounds also reversed the reduction of NR3C1 and FKBP5 in the NAc of the stressed first-generation animals, although without corresponding changes in NAc gene expression. Conclusion: Centella asiatica extract and the active compound madecassic acid have antidepressant potential, modulating the effects of chronic childhood stress in animals that experienced stress and in their offspring who were not subjected to MD and SI protocols. This potential is further supported by the observed modulation of the HPA axis changes.