The perioperative period, encompassing preoperative, intraoperative, and postoperative phases, is crucial for comprehensive patient care. During this time, the use of opioids and other drugs can lead to drug–drug interactions (DDIs), potentially resulting in adverse drug reactions (ADRs) that increase morbidity, mortality, and healthcare costs. This study investigates the drug–drug interactions (DDIs) between rocuronium, propofol, paracetamol, and lidocaine, focusing on the CYP-mediated metabolism of these drugs in the perioperative context, where these drugs are frequently co-administered. Using physiologically based pharmacokinetic (PBPK) modeling through the GastroPlus™ software and in vitro experiments with Hep G2 cells, we aimed to assess potential toxicities and pharmacokinetic interactions. Cellular viability assays revealed significant toxicity when lidocaine was combined with propofol and rocuronium, while paracetamol exhibited no considerable impact on viability. PBPK simulations confirmed moderate interactions with rocuronium and weak interactions with propofol but no relevant interactions with paracetamol. These findings emphasize the need for dose adjustments in perioperative settings to enhance patient safety, particularly with propofol and rocuronium, while supporting the co-administration of lidocaine and paracetamol. These findings show the importance of moving towards a personalized medicine model, adjusting the clinical use of lidocaine according to individual patient needs, thus promoting safer and more effective perioperative care and moving beyond the “one-size-fits-all” approach in anesthetic management.