Objective This study aimed to investigate the antipyretic and anti-inflammatory effects and mechanisms of Sanchen Pediatric antipyretic Paste (SPAP). Methods Rats were randomly divided into 7 groups: negative control group, positive control group, positive treatment group, SPAP high-dose, medium-dose and low-dose groups, and blank substrate group. Except normal control group, rats in other groups were subcutaneously injected with 10% dry yeast suspension (10 mL/kg) on the back to establish a fever model, and the normal group was given the same volume of saline. At the 4 h and 7 h after modeling, each treatment group was subjected to corresponding SPAP intervention. Anal temperature was measured every one hour after modeling for 10 consecutive times. The average temperature-rise curve, maximum temperature and body temperature response index (TRI) were calculated to evaluate the efficacy of SPAP. After the last temperature measurement, abdominal aortic blood was collected, and serum was separated from blood. The levels of IL-6, TNF-alpha and CRP in serum were determined by enzyme-linked immunosorbent assay. Results The body temperature of the positive control group was significantly increased (p < 0.01) 4 hours after model establishment, and that of the SPAP groups significantly decreased (p < 0.01) after 5 hours of the model establishment. The levels of Serum IL-6, TNF-alpha and CRP were significantly decreased (p < 0.01) in a dose-dependent manner. Conclusion SPAP has an obvious antipyretic effect on fever caused by dry yeast in rats. One of its antipyretic mechanisms may be associated with inhibiting inflammatory reactions by reducing the production or accelerating the degradation of endogenous thermogenic cytokines, such as IL-6, TNF-alpha, and CRP.