BackgroundPharmacists have been co-located in general practice teams to support the quality use of medicines and optimise patient health outcomes. Evidence of the impact of pharmacist-led activities in Australian general practices is sparse.AimThis study aimed to evaluate the potential outcomes of pharmacist-led activities in Australian general practices.MethodA prospective observational study was conducted in eight general practices in the Australian Capital Territory, where each general practice employed a pharmacist on a part-time basis for 18 months. A recommended, but flexible, list of activities was provided for pharmacists. Descriptive information on general practice pharmacist-led activities, collected with an online diary, was analysed. The potential clinical, economic, and organisational impact of pharmacist-led clinical activities was evaluated using the CLinical Economic Organisational (CLEO) tool, with a modified economic dimension.ResultsNine pharmacists reported 4290 activities over 3918.5 work hours in general practice. Medication management services were the primary clinical activity of pharmacists. In medication reviews, 75% of the pharmacists’ recommendations were fully accepted by general practitioners. Conducting clinical audits, updating patients’ medical records, and providing information to patients and staff were other major activities of pharmacists. Of 2419 clinical activities, around 50% had the potential for a moderate or major positive clinical impact on patients. Sixty-three per cent of activities had the potential to decrease healthcare costs. Almost all the pharmacist-led clinical activities had a positive organisational impact.ConclusionMost pharmacist-led clinical activities in general practice had the potential for a positive impact on patients and reduction in healthcare costs, supporting the expansion of this model in Australia.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11096-023-01604-x.