Background In Belgium, current research on socio-economic inequalities in the coronavirus disease 2019 (COVID-19) crisis has mainly focused on excess mortality and data from the first epidemiological wave. The current study adds onto this by examining the association between COVID-19 incidence and area deprivation during the first five wave and interwave periods, thus adding a temporal gradient to the analyses. Methods We use all confirmed COVID-19 cases between March 2020 and June 2021 in Belgium, aggregated at the municipality-level. These data were collected by the national laboratory-based COVID-19 surveillance system. A level of area deprivation was assigned to each Belgian municipality using data of three socio-economic variables: the share of unemployed persons in the active population, the share of households without a car and the share of low-educated persons. The spatio-temporal association between COVID-19 incidence and area deprivation was assessed by performing multivariate negative-binomial regression analyses and computing population attributable fractions. Results A significant association between COVID-19 incidence and area deprivation was found over the entire study period, with the incidence in the most deprived areas predicted to be 24% higher than in the least deprived areas. This effect was dependent on the period during the COVID-19 crisis. The largest socio-economic inequalities in COVID-19 infections could be observed during wave 2 and wave 3, with a clear disadvantage for deprived areas. Conclusion Our results provide new insights into spatio-temporal patterns of socio-economic inequalities in COVID-19 incidence in Belgium. They reveal the existence of inequalities and a shift of these patterns over time.