The 'dopamine (DA) deficit' theory is pivotal in understanding the pathogenesis of attention deficit hyperactivity disorder (ADHD). However, the relationship betweeen an imbalance in the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) the DA deficit remains poorly understood. Using the internationally recognized spontaneously hypertensive rats (SHRs) models, we investigated how a high oxidative stress (OS) state in vivo disrupts DAT-VMAT2 transport balance, a key factor influencing DA homeostasis. Our findings revealed abnormal levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), catalase (CAT), total antioxidant capacity (T-AOC), glutathione (GSH), and tumor necrosis factor-α (TNF-α) in SHRs. Furthermore, the antioxidative stress-related nuclear factor erythroid 2-related factor (Nrf2)/kelch-like ECH-associated protein 1 (Keap-1)/heme oxygenase-1 (HO-1) pathway was inhibited, leading to excessive DAT activation and functional antagonism of VMAT2. Notably, Baicalin (BA) ameliorated these imbalances. Treatment with the VMAT2 inhibitor tetrabenazine (TBZ) exacerbated VMAT2 inhibition in SHRs brains, further activating DAT and restricting Nrf2 nuclear translocation. These results confirmed the strong link between the Nrf2/Keap-1/HO-1 pathway the DAT-VMAT2 imbalance. Moreover, under high OS conditions, the phosphorylation of nuclear factor-κB P65 (NF-κB P65) was triggered, leading to the upregulation of heat shock cognate protein 70 (HSC70). We aslo identified a potential negative feedback mechanism between HSC70 and VMAT2. In summary, our study uncovered a novel mechanism in ADHD pathogenesis, demonstrating that the DA deficits resulted from an imbalance between DAT and VMAT2. Remarkably, BA significantly reduced high levels of OS and inflammation by activating the Nrf2/Keap-1/HO-1 pathway, thereby restoring DAT-VMAT2 transport balance and enhancing DA homeostasis. This discovery provides a solid foundation for further exploration of ADHD pathogenesis and offers new molecular insights for ADHD treatment.