IntroductionThe outbreak of the COVID-19 global pandemic in 2020 has been a major challenge for the world’s population and governments. The lack of vaccines, the saturation of health systems, and its rapid spread forced governments to take non-pharmacological interventions (NPI) that had a high impact on the population. Assessing the efficacy of these measures is a challenge for health technology assessment bodies.MethodsThe main NPIs for which assessment was required were: mobility restrictions, social distancing, cancellation of events or reduction of seating capacity, closure or reduction of seating capacity in non-essential businesses, closure or limitation of seating capacity in educational establishments, and promotion of teleworking in potential jobs. The implementation of these measures at a global level provides a large population for the study of the impact of these measures. However, the challenges for their evaluation are numerous: •The joint implementation of these measures makes it difficult to evaluate them in an isolated manner.•The heterogeneity between countries and regions of the pandemic situation at the time when these measures are initiated and terminated.•The different accuracy in the application of the measures.•Heterogeneity in the quality and accessibility of public health services for citizens.ResultsOutcome variables to assess the effectiveness of these measures should include parameters related to:•Incidence variables: the number of new or accumulated cases in a given time range, the variation in the number of cases in a given time range and the proportion of positive tests.•Transmission variables: the basic reproductive number (R0) and the effective reproductive number (Rt).•Severity and mortality variables: the number or variation of hospitalizations, the number or variation of intensive care unit (ICU) hospitalizations and the number or variation of deaths.ConclusionsThe large number of available data, the heterogeneity of the measures, the differences between populations, the numerous outcome variables and the possible inclusion of mathematical modelling studies, are a methodological challenge for the HTA bodies.