ABSTRACT Purpose In clinical practice, a discrepancy may exist between the prescribed amount of a drug and the commercially available pack sizes in the pharmacy, potentially contributing to drug waste. This study aimed—as an example of this phenomena—to quantify leftover of amoxicillin suspension prescribed to children, due to discrepancies between physician‐prescribed and pharmacy‐dispensed amounts. Methods We performed a retrospective cohort study including amoxicillin suspension dispensations for patients aged 0–12 years between 2017 and 2019 utilizing the Dutch PHARMO database. Leftover amount of amoxicillin was estimated by assessing the discrepancy between the prescribed and dispensed amounts. Extrapolated amoxicillin weight and economic spillage estimates for the Netherlands were determined. The impact of two theoretical interventions on leftover amount was assessed: (1) introducing vials with half the volume of the current 100 and 30 mL vials and (2) a combination of the first intervention with a maximum of 10% round‐down by the dispensing pharmacy of the prescribed dose. Results We included 79 512 amoxicillin suspension dispensations for 62 252 patients. The mean leftover amount of amoxicillin suspension per dispensing was 27%. The yearly amount of amoxicillin leftover was 49.8 kg in the study cohort, equivalent to yearly 633 kg and €621 000 when extrapolated to the Netherlands. Employing the first theoretical intervention reduced the mean leftover per dispensing to 20%, reducing the yearly leftover to 31.6 kg amoxicillin in the study cohort, and to 400 kg and €400 000 extrapolated. The second theoretical intervention further reduced leftover to 17%, reducing the yearly leftover to 24.3 kg amoxicillin in the study cohort, and to 300 kg and €300 000 extrapolated. Conclusion Approximately a quarter of amoxicillin suspension remains as leftover per dispensing. Applying different theoretical intervention shows the potential for a significant reduction of amoxicillin leftover.