The Croatian Agency for Medicines and Medical Products, as the only authorized body in Republic of Croatia, annually publishes a report on expenditure of medicines for the previous year. Reports include consumption according to defined daily doses and financial expenditure respecting pharmacoeconomic principles. Pharmacoeconomics is an economic discipline that determines the costs of drugs over time and compares the actual effects of pharmaceutical products and health programs. This research analysed medicine expenditure in the period before and during the COVID-19 pandemic (2019–2022) with the aim of determining whether the pandemic had a significant impact on drug expenditure in the country. Data was processed using data analysis methods alongside application of the Weka program. Results show that for out-of-hospital consumption of medicines, there were no significant oscillations in daily doses, and a slight growth trend was noted for all groups of medicines. In contrast, significant financial growth was recorded, mostly in group J (stimulated by vaccines for COVID-19) and particularly expensive drugs from group L (drugs for rare and serious diseases). The increase in drug consumption can be attributed to general aging of the population, constant development of the pharmaceutical industry (especially generic and innovative smart drugs) and tendency to use pharmaceuticals more often. However, the increase in drug prices alone is mostly the result of general inflation in the global economy indirectly stimulated by the COVID-19 pandemic and recent war events in the world. Overall, the results of this research indicate that COVID-19 pandemic did not significantly affect the outpatient and hospital consumption of drugs for individual therapeutic groups in the Republic of Croatia. The Croatian health system withstood the pressure of the pandemic and, in parallel, maintained the function of treating other population health needs.