The use of sanctions as a policy tool to affect change in the political behavior of target states has increased over the past 30 years, along with a concern about their impact on civilian health. Some researchers have proposed that targeting sanctions can avoid their moral costs, yet others have challenged this claim. This systematic mixed-studies review explored the debate about targeted sanctions by appraising their health effects as reported in the medical and public health literature, with a global focus and through the COVID-19 era. We searched three electronic databases without temporal or geographical restrictions and identified 50 studies spanning three decades (1992–2021) meeting our inclusion criteria. Using a piloted form, we extracted quotations addressing our research questions and identified themes that we grouped according to the effects of sanctions on health or its determinants, generating frequency distributions to assess the strength of support for each theme. While no study posited a causal relationship between sanctions and health, or engaged the morality of sanctions, most implied that when sanctions were present, health was inevitably impacted, even for sanctions ostensibly targeted to minimize civilian harm. Our findings suggest that given the integrated nature of the global economy, it is all but impossible to design sanctions that will achieve their stated goals without inflicting significant harm on civilians. We conclude that the use of sanctions as a policy tool threatens global health and human rights, especially in times of crises.