This study investigated the effects of citrus flavonoids (CF) and compared to antibiotics on piglet growth and gut health. Weaned piglets were fed either a basal diet (CON) or a basal diet supplemented with 75 mg/kg chlortetracycline (CTC), 20 mg/kg CF (CF1), 40 mg/kg CF (CF2), or 80 mg/kg CF (CF3). The CF group, especially CF3, exhibited improved growth performance; reduced diarrhea; significantly higher levels of serum growth factors, immunoglobulins, and anti-inflammatory cytokines; and significantly lower levels of pro-inflammatory factors and markers of intestinal barrier damage ( < 0.05). The intestinal mucosa proteins ZO-1 and occludin increased, while NF-κB and TLR2 decreased, correlating with CF dosage ( < 0.05). Furthermore, CF promoted a favorable balance in the gut microbiota, with an increased relative abundance of and and decreased taxa and . Overall, CF enhanced piglet growth and gut health by modulating the TLR2/NF-κB pathway, offering a natural antibiotic alternative. The optimal dose of CF was 80 mg/kg.