BACKGROUND: Multimorbidity, the presence of more than one condition in a single individual, is a global health issue in primary care. Multimorbid patients tend to have a poor quality of life and suffer from a complicated care process. Clinical decision support systems (CDSSs) and telemedicine are the common information and communication technologies that have been used to reduce the complexity of patient management. However, each element of telemedicine and CDSSs is often examined separately and with great variability. Telemedicine has been used for simple patient education as well as more complex consultations and case management. For CDSSs, there is variability in data inputs, intended users, and outputs. Thus, there are several gaps in knowledge about how to integrate CDSSs into telemedicine and to what extent these integrated technological interventions can help improve patient outcomes for those with multimorbidity. OBJECTIVE: Our aims were to (1) broadly review system designs for CDSSs that have been integrated into each function of telemedicine for multimorbid patients in primary care, (2) summarize the effectiveness of the interventions, and (3) identify gaps in the literature. METHODS: An online search for literature was conducted up to November 2021 on PubMed, Embase, CINAHL, and Cochrane. Searching from the reference lists was done to find additional potential studies. The eligibility criterion was that the study focused on the use of CDSSs in telemedicine for patients with multimorbidity in primary care. The system design for the CDSS was extracted based on its software and hardware, source of input, input, tasks, output, and users. Each component was grouped by telemedicine functions: telemonitoring, teleconsultation, tele-case management, and tele-education. RESULTS: Seven experimental studies were included in this review: 3 randomized controlled trials (RCTs) and 4 non-RCTs. The interventions were designed to manage patients with diabetes mellitus, hypertension, polypharmacy, and gestational diabetes mellitus. CDSSs can be used for various telemedicine functions: telemonitoring (eg, feedback), teleconsultation (eg, guideline suggestions, advisory material provisions, and responses to simple queries), tele-case management (eg, sharing information across facilities and teams), and tele-education (eg, patient self-management). However, the structure of CDSSs, such as data input, tasks, output, and intended users or decision-makers, varied. With limited studies examining varying clinical outcomes, there was inconsistent evidence of the clinical effectiveness of the interventions. CONCLUSIONS: Telemedicine and CDSSs have a role in supporting patients with multimorbidity. CDSSs can likely be integrated into telehealth services to improve the quality and accessibility of care. However, issues surrounding such interventions need to be further explored. These issues include expanding the spectrum of medical conditions examined; examining tasks of CDSSs, particularly for screening and diagnosis of multiple conditions; and exploring the role of the patient as the direct user of the CDSS.