Background: Potentially inappropriate polypharmacy (PIP) is among the major factors leading to adverse drug reactions, increased healthcare costs, reduced medication adherence, and worsened patient conditions. This study aims to identify existing interventions implemented to monitor and manage polypharmacy in the Italian setting. Methods: A systematic literature review (PROSPERO: CRD42023457049) was carried out according to the PRISMA statement guidelines. PubMed, Embase, ProQuest, and Web of Science were queried without temporal constraints, encompassing all published papers until October 2023. Inclusion criteria followed the PICO model: patients with polypharmacy; interventions to monitor/manage polypharmacy regimen versus no/any intervention; outcomes in terms of intervention effectiveness and cost variation. Results: After duplicate deletion, 153 potentially relevant publications were extracted. Following abstract and full-text screenings, nine articles met the inclusion criteria. Overall, 78% (n = 7) were observational studies, 11% (n = 1) were experimental studies, and 11% (n = 1) were two-phase studies. A total of 44% (n = 4) of the studies involved patients aged ≥ 65 years, while 56% (n = 5) were disease-specific. Monitoring was the most prevalent choice of intervention (67%; n = 6). Outcomes were mainly related to levels of polypharmacy (29%; n = 6) and comorbidities (29%; n = 6), effectiveness rates (14%; n = 3), and avoidable costs (9%; n = 2). Conclusions: This review outlines that Italy is still lacking in interventions to monitor/manage PIP, addressing an unmet need in developing patient-tailored strategies for reducing health-system burden.