Background: Challenges of polypharmacy and the impact of coronavirus disease 2019 (COVID-19) pandemic in older patients require further investigation. This retrospective study analyzed the progression of polypharmacy and anticholinergic burden in older patients in a primary care setting before, during, and after the COVID-19 pandemic. Methods: This 3-year cross-sectional study (2019, 2020, and 2021) comprised a dynamic cohort of individuals aged ≥75 years, who attended the Arrabal Primary Care Center in Zaragoza, Spain. Older patients with polypharmacy (≥5 medications) were identified according to their electronic health records. We collected demographic and clinical data, including medication prescriptions, diagnoses, and anticholinergic risks, and performed descriptive and statistical analyses. Results: This study included a total of 1,928 patients with a mean age of 83.52±0.30 years. Over the 3-year study period, the mean number of medications prescribed increased, from 9.4 in 2019 to 10.4 in 2021. The prevalence of excessive polypharmacy (≥10 medications) increased from 39% in 2019 to 45% in 2021. The most commonly prescribed drugs were anilides, proton pump inhibitors, benzodiazepine derivatives, and platelet aggregation inhibitors. Women had a higher prevalence of illnesses and anticholinergic drug prescriptions than men. Conclusion The results of this study highlighted an upward trend in polypharmacy and excessive polypharmacy among older patients in primary care settings. Future research should focus on optimizing medication management and deprescribing strategies and minimizing the adverse effects of polypharmacy in this population.