Abstract: Background: Premenstrual dysphoric disorder (PMDD), a subtype of premenstrual syndrome (PMS), involves physical and emotional symptoms that impact patients' daily lives and productivity. A reliable, side-effect-free clinical intervention is needed. Shuyu capsule is an effective traditional Chinese medicine preparation for PMDD used in clinics, but its therapeutic mechanism remains unclear. Previous research has suggested that the gamma-aminobutyric acid (GABAergic) system in the periaqueductal gray (PAG) may play a role in treating PMDD with traditional Chinese medicine, but functional verification is lacking. Purpose: This study aims to reveal the potential mechanism of the Shuyu capsule in treating PMDD. Study design: The study employed an experimental design using female C57BL/6J and Vgat Cre mice to assess the effects of Shuyu capsules on PMDD, focusing on the GABAergic system in the dorsal periaqueductal gray (dPAG). Methods: Assessments were conducted using the Forced Swimming Test (FST) to gauge depressive-like behaviours and Western blot (WB) and immunofluorescence (IF) to measure the numbers of active GABAergic neurons and the gamma-aminobutyric acid type A receptor (GABA_AR) δ subunit expressions. Chemogenetic techniques and adeno-associated virus were specifically used to activate GABAergic neurons and knock down the expression of subunits, respectively, providing insights into the neurobiological mechanisms underpinning the therapeutic effects of Shuyu capsules in treating PMDD. Results: After being stressed by forced swimming, the immobility duration of PMDD mice in the late dioestrus (LD) phase increased after the Shuyu capsule intervention, implying that it can improve the oestrous cycle-dependent depression-like phenotype in PMDD mice. Additionally, the application of Shuyu can down-regulate the expression of GABA type A receptor δ subunit (GABRD) and reverse the downtrend of activated GABAergic neurons in the dPAG of PMDD model mice. We also found that single target manipulation was enough to improve the depression-like behaviour of PMDD model mice. Transgenic mice with GABRD knockout were established, and their behaviours were tested, revealing changes in their exploratory behaviours, indicating that the GABA_AR δ subunit may be closely related to anxiety diseases. Conclusion: Shuyu capsule plays an anti-PMDD role by activating GABAergic neurons and down-regulating the expression of GABRD in the dPAG. This provides a theoretical basis for the clinical treatment of PMDD with traditional Chinese medicine and promotes the development of drugs for treating PMDD.