Background: Internationally, governments have been investing in supporting pharmacists to take on an expanded role to support self-care for health system efficiency. There is consistent evidence that minor ailment schemes (MASs) promote efficiencies within the health care system. The cost savings and health outcomes demonstrated in the United Kingdom and Canada open up new opportunities for pharmacists to effect sustainable changes through MAS delivery in Australia. Objective: This trial aims to evaluate the clinical, economic, and humanistic impact of an Australian Minor Ailments Service (AMAS) compared with usual pharmacy care in a cluster randomized controlled trial (cRCT) in Western Sydney, Australia. Methods: The cRCT design has an intervention group and a control group, comparing individuals receiving a structured intervention (AMAS) with those receiving usual care for specific health ailments. Participants will be community pharmacies, general practices, and patients located in Western Sydney Primary Health Network (WSPHN) region. A total of 30 community pharmacies will be randomly assigned to either intervention or control group. Each will recruit 24 patients, aged 18 years or older, presenting to the pharmacy in person with a symptom-based or product-based request for one of the following ailments: reflux, cough, common cold, headache (tension or migraine), primary dysmenorrhea, or low back pain. Intervention pharmacists will deliver protocolized care to patients using clinical treatment pathways with agreed referral points and collaborative systems boosting clinician-pharmacist communication. Patients recruited in control pharmacies will receive usual care. The coprimary outcomes are rates of appropriate recommendation of nonprescription medicines and rates of appropriate medical referral. Secondary outcomes include self-reported symptom resolution, health services resource utilization, and EuroQoL Visual Analogue Scale. Differences in primary outcomes between groups will be analyzed at the individual patient level accounting for correlation within clusters with generalized estimating equations. The economic impact of the model will be evaluated by cost-utility and cost-effectiveness analysis compared with usual care. Results: The study began in July 2018. Thirty community pharmacies were recruited. Pharmacists from the 15 intervention pharmacies were trained. A total of 27 general practices consented. Pharmacy patient recruitment began in August 2018 and was completed on March 31, 2019. Conclusions: This study may demonstrate the efficacy of a protocolized intervention to manage minor ailments in the community and will assess the clinical, economic, and humanistic impact of this intervention in Australian pharmacy practice. Pharmacists supporting patient self-care and appropriate self-medication may contribute to greater efficiency of health care resources and integration of self-care in the health system. The proposed model and developed educational content may form the basis of a national MAS service in Australia, using a robust framework for management and referral for common ailments. Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618000286246; http://www.anzctr.org.au/ACTRN12618000286246.aspx International Registered Report Identifier (IRRID): DERR1-10.2196/13973 We help JMIR researchers to raise funds to pursue their research and development aimed at tackling important health and technology challenges. If you would like to show your support for this author, please donate using the button below. The funds raised will directly benefit the corresponding author of this article (minus 8% admin fees). Your donations will help this author to continue publishing open access papers in JMIR journals. Donations of over $100 may also be acknowledged in future publications. Suggested contribution levels: $20/$50/$100 [ABSTRACT FROM AUTHOR]