(1) Background: Antibiotic resistance is a worldwide health threat. The WHO published a global strategic plan in 2001 to contain antimicrobial resistance. In the following year, a workshop identified crucial barriers to the implementation of the strategy, e.g., underdeveloped health infrastructures and the scarcity of valid data as well as a lack of implementation of antibiotic stewardship (ABS) programs in medical curricula. Here, we show that interprofessional learning and education can contribute to the optimization of antibiotic use and preserving antibiotic effectiveness. We have initiated interprofessional rounds on a medical intensive care unit (MICU) with a focus on gastroenterology, hepatology, infectious diseases, endocrinology, and liver transplantation. We integrated ICU physicians, hospital pharmacists, nursing staff, and medical students as well as students of pharmacy to broaden the rather technical concept of ABS with an interprofessional approach to conceptualize awareness and behavioral change in antibiotic prescription and use. Methods: Clinical performance data and consumption figures for antibiotics were analyzed over a 10-year period from 2012 to 2021. The control period covered the years 2012-2014. The intervention period comprised the years 2015-2021, following the implementation of an interprofessional approach to ABS at a MICU of a German university hospital. Data from the hospital pharmacy, hospital administration, and hospital information system were included in the analyses. A specific electronic platform was developed for the optimization of documentation, interprofessional learning, education, and sustainability. The years 2020 and 2021 were analyzed independently due to the SARS-CoV-2 pandemic and the care of numerous COVID-19 patients at the MICU. Results: Implementation of an interprofessional ABS program resulted in the optimization of antibiotic management at the MICU. The suggestions of the hospital pharmacist for optimization can be divided into the following categories (i) indication for and selection of therapy (43.6%), (ii) optimization of dosing (27.6%), (iii) drug interactions (9.4%), (iv) side effects (4.1%), and (v) other pharmacokinetic, pharmacodynamic, and pharmacoeconomic topics (15.3%). These suggestions were discussed among the interprofessional team at the MICU; 86.1% were consequently implemented and the prescription of antibiotics was changed. In addition, further analysis of the intensive care German Diagnosis Related Groups (G-DRGs) showed that the case mix points increased significantly by 31.6% during the period under review. Accordingly, the severity of illness of the patients treated at the ICU as measured by the Simplified Acute Physiology Score (SAPS) II increased by 21.4% and the proportion of mechanically ventilated patients exceeded 50%. Antibiotic spending per case mix point was calculated. While spending was EUR 60.22 per case mix point in 2015, this was reduced by 42.9% to EUR 34.37 per case mix point by 2019, following the implementation of the interprofessional ABS program on the MICU. Through close interprofessional collaboration between physicians, hospital pharmacists, and staff nurses, the consumption of broad-spectrum antibiotics, e.g., carbapenems, was significantly reduced, thus improving patient care. In parallel, the case mix and case mix index increased. Thus, the responsible use of resources and high-performance medicine are not contradictory. In our view, close interprofessional and interdisciplinary collaboration between physicians, pharmacists, and nursing staff will be of outstanding importance in the future to prepare health care professionals for global health care to ensure that the effectiveness of our antibiotics is preserved.