Mycotoxin exposure and enteric bacterial overgrowth often coincide in broiler production, compromising performance and gut barrier function. Accordingly, multicomponent toxin binders (MTB) and organic acid blends (OAB) warrant integrated in vivo evaluation under concurrent challenge with aflatoxin B1 (AFB1) and Clostridium perfringens. To assess the efficacy of MTB alone or in combination with OAB under these dual challenges, a 42-day trial was conducted using 420 day-old broiler chickens assigned to seven treatments (6 replicates × 10 birds): control (unchallenged), A (AFB1), AM (AFB1 + MTB), AMO (AFB1 + MTB + OAB), AC (AFB1 + C. perfringens), ACM (AFB1 + C. perfringens + MTB), and ACMO (AFB1 + C. perfringens + MTB + OAB). AFB1 (500 ppm) was fed on days 0–42; C. perfringens (1 × 108 CFU/mL) was administered on days 15–24. Compared to control, AFB1 and C. perfringens significantly reduced body weight gain (BWG) and the European Production Efficiency Index (EPEI), with AM mitigating these effects. In the co-challenge scenario, AC further impaired BWG and EPEI, while ACMO restored feed conversion ratio and EPEI to levels comparable to control during days 25–42. Nutrient digestibility and villus metrics declined under both challenges. AC increased C. perfringens counts, while AM and ACMO mitigated these effects and normalized the villus-to-crypt ratio by day 42. The combined AFB1 and C. perfringens challenge reduced ZO-1 expression, but supplementation with MTB and OAB restored ZO-1 and occludin levels to control values and tended to increase JAM-2 expression. In conclusion, co-exposure to AFB1 and C. perfringens produced more severe impairments than AFB1 alone; MTB was protective, and its combination with OAB enhanced mitigation against both challenges.