Introduction Telemedicine is increasingly used to deliver healthcare in many clinical specialities. However, the adoption of telemedicine in the delivery of outpatient parenteral antimicrobial therapy (OPAT) has been relatively slow and limited. This study aims to collate current evidence for telemedicine in OPAT regarding clinical efficacy, safety, acceptability and cost-effectiveness. Methods We systematically searched the Cochrane Library, CINAHL, EMCARE, EMBASE and MEDLINE databases through 24 July 2022, for relevant studies published in English. Research articles and conference abstracts were included if they involved any form of telephone or video consultation in delivering parenteral antibiotics in the home or outpatient setting. Study findings were synthesised into three main themes: patient outcomes and safety, patient and provider satisfaction and cost-effectiveness. The mixed methods appraisal tool was used to review the methodological quality of the studies. PROSPERO CRD42022342874 Results The literature search yielded 311 articles, of which 12 (five full-length articles and seven conference abstracts) reporting over 1245 telemedicine interventions were reviewed. The reported outcomes were heterogeneous. Telemedicine was cost-effective and associated with high patient satisfaction and comparable complication rates compared to conventional OPAT. Considering six comparative studies, rehospitalisation risk was lower for telemedicine than conventional OPAT (risk ratio, 0.58; 95% confidence interval, 0.38–0.88; I2 = 31%). Discussion The results of this review demonstrate that telemedicine has a role in delivering safe and cost-effective OPAT care, especially for patients residing in remote and geographically isolated locations. Nevertheless, high-quality studies and publication of existing data and experiences are needed to further validate this model of care delivery.