Abstract Background Medication administration errors (MAEs) occur frequently in hospitals and may compromise patient safety. Preventive strategies are needed to reduce the risk of MAEs. Objective The primary aim of this study was to assess the effect of central automated unit dose dispensing with barcode-assisted medication administration on the prevalence of MAEs. Secondary aims were to assess the effect on the type and potential severity of MAEs. Furthermore, compliance with procedures regarding scanning of patient and medication barcodes and nursing staff satisfaction with the medication administration system were assessed. Methods We performed a prospective uncontrolled before-and-after study in six clinical wards in a Dutch university hospital from 2018 to 2020. MAE data were collected by observation. The primary outcome was the proportion of medication administrations with one or more MAEs. Secondary outcomes were the type and potential severity of MAEs, rates of compliance with patient identification and signing of administered medication by scanning and nursing staff satisfaction with the medication administration system. Multivariable mixed-effects logistic regression analyses were used for the primary outcome to adjust for confounding and for clustering on nurse and patient level. Results One or more MAEs occurred in 291 of 1490 administrations (19.5%) pre-intervention and in 258 of 1630 administrations (15.8%) post-intervention (adjusted odds ratio 0.70, 95% confidence interval 0.51–0.96). The rate of omission fell from 4.6% to 2.0% and of wrong dose from 3.8% to 2.1%, whereas rates of other MAE types were similar. The rate of potentially harmful MAEs fell from 3.0% (n = 44) to 0.3% (n = 5). The rates of compliance with scanning of patient and medication barcode post-intervention were 13.6% and 55.9%, respectively. The median overall satisfaction score of the nurses with the medication administration system on a 100-point scale was 70 (interquartile range 63–75, n = 193) pre-intervention and 70 (interquartile range 60–78, n = 145) post-intervention (P = 0.626, Mann–Whitney U test). Conclusion The implementation of central automated unit dose dispensing with barcode-assisted medication administration was associated with a lower probability of MAEs, including potentially harmful errors, but more compliance with scanning procedures is needed. Nurses were moderately satisfied with the medication administration system, both before and after implementation. In conclusion, despite low compliance with scanning procedures, this study shows that this intervention contributes to the improvement of medication safety in hospitals.