Foot-and-mouth disease (FMD) vaccine does not afford early effective protection until adaptive immune protection caused by the vaccination occurs. Therefore, an alternative prophylactic application of antiviral agents for inhibition of the FMD virus is needed, and this is the scope of this study. In this study, we tested nine adamantane-pyrazole derivatives that could exhibit antiviral activity against FMDV infection either in vitro through baby hamster kidney cells (BHK-21 cells) infected with FMD virus serotypes O pan Asia. Cytotoxicity Concentration 50 (CC₅₀) activity of pyrazole derivatives (1, 2, 3, 4, 5a,b, 6a-c) were detected on BHK-21 cells and ranged between 500 to 3000µg/ml. Inhibitory Concentration 50 (IC₅₀) on BHK-21 was achieved only for the most promising three derivatives 6a-c and exhibited an antiviral activity with a therapeutic index of 30, and that was reflected on the antiviral activity response in baby mice with different concentrations where a concentration of 50 µg/ml for pyrazole derivatives 6a and 6c compounds and 40 µg/ml for bis-tolyl pyrazole 6b that achieve 100% protection and this results was as effective as 50 µg/ml of amantadine. Specifically, diaryl pyrazole derivatives 6a-c that protected for six days following FMDV challenge. These results suggested that pyrazole derivatives 6a-c could be used as an effective antiviral agent against FMD virus infection. Molecular docking simulation of the target compounds 6a-c had good binding energy and the tested compounds recommended being an excellent 3C protease inhibitor compared to Amantadine and Ribavirin. These findings may explain the antiviral activity of the target compounds.