Leptin, as a hormone secreted from adipose tissue, plays an important role in the homeostasis of energy consumption (Obradovic et al., 2021) and an obesity (Monteiro et al., 2022) that commonly associated with hypertension (Perdomo et al., 2023; Arabi et al., 2022). Large number of literatures have been documented that Leptin also participate in the blood pressure (BP) regulation centrally (Buncha et al., 2023; Matsumura et al., 2003) or peripherally (Kim et al., 2023) through its receptor (OB-Rs such as OB-Ra or OB-Rb). Clinical data indicates that a serum concentration of Leptin is significantly higher in patients with hypertension (Ofori et al., 2023). Clinical evidence also reveals that Leptin is closely related to the central sympathetic excitation (Liu and Zheng, 2021) due at least partially to increase the production of α-melanocyte-stimulating (α-MSH) (Mark et al., 2009) in baroreflex afferent pathway via its receptors (MC3R/MC4R), leading to the hypertension with a sexual dimorphism in the OB-R down-regulation (Coatmellec-Taglioni et al., 2003). Additionally, Leptin concentration required for renal sympathetic activation is largely lowered than that of centrally administration causing a BP elevation observed by intracerebroventricular injection of Leptin, implying that a multiple mechanisms maybe involved in Leptin-mediated BP homeostasis. Interestingly, BP elevation is not confirmed by acute application of Leptin instead of increase in a peripheral blood flow (Trovati et al., 2014) and coronary vasodilation (Matsuda et al., 2003) with/without nitric oxide involvement, suggesting that Leptin-mediated sympathetic activation and BP elevation are somehow buffered off by an unknown hypotensive mechanism likely to be mediated through baroreflex afferent function (Santa Cruz Chavez et al., 2014). For this regard, our immediate question to be answered by this investigation is whether or not direct microinjection of Leptin into the nodose ganglion (NG), the location of the 1st-order baroreceptor neurons within the baroreflex afferent pathway. Clearly, the results from the current study demonstrated for the first time that NG microinjection of Leptin induced BP reduction, rather than elevation, in age-matched adult male and female rats dose-dependently, which is supported by the fact that a strong membrane depolarization or inward current induced by direct activation of female-specific subpopulation of myelinated Ah-type neurons with Leptin; whereas, increased serum concentration of Leptin and down-regulated Leptin receptor were further detected in the NG and NTS under hypertensive condition, highly suggesting that Leptin/its receptor play an important role in BP homeostasis via direct baroreflex afferent function under both physiological and hypertensive condition. This result provides additional information to fully understand plausible role of Leptin in BP homeostasis and clinical management of hypertension.