We advance and test an institutional anomie theory of opportunity entrepreneurship for understanding the combinative effects of selected cultural values and social institutions to explain national differences in rates of opportunity entrepreneurship. We theorize opportunity entrepreneurship as a creatively deviant response to anomic conditions in societies, i.e., when social institutions block traditional means of achievement. Using 10 years of data for a pooled time series cross‐sectional analysis, we examined a unique mixture of cultural and institutional variables and their interactions as predictors of nation‐level opportunity entrepreneurship rates. We found support for most hypotheses showing that specific institutional contexts mitigate or enhance the effects of cultural drivers of opportunity entrepreneurship.