The Sanhuanglianqiao mixture (SHLQ) was prepared from a certain proportion of Scutellaria baicalensis Georgi, Forsythia suspensa, and Rheum palmatum L and obtained by water extraction and alcohol precipitation. This study explored the effects of SHLQ on Penaeus vannamei and its protective role against Vibrio parahaemolyticus (V. parahaemolyticus) infection. The results indicated that the main active components of SHLQ, namely baicalin, phillyrin, and emodin, had concentrations of 7.34 mg/mL, 4.01 mg/mL, and 32.95 μg/mL, respectively. SHLQ significantly enhanced shrimp growth performance and digestive enzyme activities. Mechanistically, SHLQ augmented innate immunity by upregulating immune-related genes and boosting antioxidant defenses in hepatopancreas and hemolymph. Concurrently, SHLQ reshaped gut microbiota diversity, suppressing pathogenic Vibrionaceae while enriching beneficial taxa, thereby reinforcing metabolic and immune functions. Critically, SHLQ alleviated V. parahaemolyticus-induced intestinal/hepatopancreatic damage, increased hemolymph cell viability, and reduced apoptosis caused by the virulence factor rPirB. These synergistic effects-combining immunomodulation, microbiota regulation, and tissue protection-collectively improved shrimp survival rates. Our findings highlight SHLQ as a promising multi-target agent against V. parahaemolyticus infection in aquaculture.