Background: Antimicrobial resistance (AMR) is a major global health concern, and antimicrobial stewardship (AMS) programs have emerged as essential strategies to optimize antibiotic use. Pharmacists play a central role in implementing AMS interventions across diverse healthcare settings. This systematic review aimed to evaluate the impact of pharmacist-led and multidisciplinary AMS interventions on prescribing practices, adherence to guidelines, and clinical outcomes. Methods: A comprehensive search of PubMed, Scopus, Web of Science, and Google Scholar was conducted to identify eligible studies. Randomized controlled trials, cluster randomized trials, prospective studies, cross-sectional surveys, and protocols were included if they examined pharmacist or multidisciplinary AMS interventions. Data extraction and quality assessment were performed independently by two reviewers. Results: Eight studies published between 2005 and 2023 were included, spanning hospital, community, and primary care settings across multiple countries. Interventions assessed included pharmacist-led post-prescription review, educational programs, guideline reinforcement, and multifaceted communication strategies. Findings consistently demonstrated improvements in prescribing appropriateness, reductions in unnecessary antibiotic use, and enhanced adherence to guidelines. Clinical outcomes such as mortality, hospital stay, and treatment success were either comparable or improved, without compromising patient safety. However, cost effectiveness outcomes were variable, with some interventions associated with higher treatment costs due to increased use of broad-spectrum agents. Conclusion: Pharmacist-led and multidisciplinary AMS interventions are effective in improving antibiotic prescribing quality and supporting rational use across healthcare settings. Expanding pharmacists’ roles within AMS teams, supported by governance, education, and adequate resources, is crucial to strengthen stewardship programs and reduce the global burden of AMR.