During the COVID-19 pandemic, governments have advocated numerous social distancing measures, and compliance with these has likely saved millions of lives globally. In an online sample drawn from the U.S. and Canada (N = 209), participants completed measures of political orientation, moral foundations, and COVID-19 social distancing attitudes and behaviours. A more left-wing political orientation, and greater endorsement of the individualizing moral foundations were significantly related to more positive social distancing attitudes, and greater self-reported compliance with relevant restrictions. A more right-wing political orientation, and greater endorsement of the binding and economic liberty foundations were associated with less positive attitudes and reduced compliance. In a series of mediation analyses, the relationships between political orientation and various social distancing measures were significantly mediated by variations in participants’ moral foundations, particularly their endorsement of economic liberty and the individualizing foundations. Further data indicated that the perceived persuasiveness of messages based on each moral foundation advocating for continued social distancing was significantly related to both participants’ moral values and their political orientation. Findings are discussed in terms of understanding politicized differences around social distancing as partly reflecting differential valuation of the moral foundations, and in creating effective public health messaging regarding compliance.