Calcium oxide and small amount of alumina powders were mechanically milled in a planetary ball milling system using ZrO2 pot and balls, in order to refine the sizes of the powders and promote the reactions between the raw powders. The obtained powders were subjected to an accelerated degradation test in CO2/H2O atmosphere, and the antiviral activity was evaluated by using an avian influenza virus strain (H5N3). The mechanically milled powders revealed a significant improvement in durability of antiviral activity after the powders were hydrated. One of the reasons seems to be associated with the solid solution of Al2O3 into calcium oxide and agglomeration of the powders during the mechanical milling. Moreover, it was found that ZrO2 has an effect similar to Al2O3. The incorporation of ZrO2 in CaO by either addition of ZrO2 powder or contamination from milling media can also improve the durability of antiviral activity of CaO.