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The current experiment was designed to evaluate the effects of dietary supplementations of zinc oxide nanoparticles (ZONPs) on some behavioural, performance, welfare and histopathological changes in broilers exposed to multidrug resistant Staphylococcus aureus (MRSA)-induced footpad dermatitis (FPD). Eighty-four male Indian River (IR) broilers were randomly allotted to six different dietary treatments as follows: C-ve, C+ve, 10, 20, 30 and 40 ppm ZONPs from 7 to 49d of age. At day 28, broilers ( n  = 70) were sub-cutaneously injected with 0.5 ml of saline containing 5.3 × 10 7  CFU/ml of S. aureus (MRSA) in each metatarsal foot pad. Control (non-infected) broilers were given 0.5 ml of saline ( n  = 14). Results clarified that non-infected birds and ZONPs-fed birds had significantly higher standing and feeding activities and lower resting activities in comparison with the infected group. Also, the S. aureus infected group had significantly lower body weight gain (BWG) and higher feed conversion ratio (FCR) than the non-infected group. In addition, the non-infected birds and ZONPs groups had significantly lower object crossing and tonic immobility times (TI) and gait scores (GS) in comparison with the S. aureus group. Only ZONPs 30, 40 ppm and non-infected groups had a significantly higher latency to lie time (LLT) and lower serum cortisol level in comparison with the S. aureus group. Moreover, there were significant changes in the gross lesion score and histopathological lesions between the different groups. In conclusion, the dietary supplementation of ZONPs can reduce S. aureus -induced negative effects of FPD in broilers.