Inhalational anesthetics have been the default agents for general anesthesia maintenance for several decades. However, with advances in total intravenous anesthesia (TIVA) and a growing body of evidence on the potential benefits of TIVA, anesthesiologists need to question this paradigm. Some of the benefits of propofol-based TIVA, such as its antiemetic properties and patients’ smooth emergence, are widely acknowledged. A growing body of evidence suggests that TIVA may potentially benefit the immune system and cancer outcomes. From an existential health perspective, there is evidence that inhalational agents have a materially higher global warming potential than propofol-based TIVA. Despite the compelling potential benefits of propofol-based TIVA, there are barriers to its widespread adoption. To examine the applicability of TIVA as a mainstay agent more rigorously, we discuss the safety and applicability of propofol-based TIVA in the context of complex major abdominal surgery, specifically, liver resection surgery. We also discuss the use of propofol-based TIVA in liver resection surgery with a broad, integrated approach, addressing general and specific clinical considerations, economic factors, and operating room turnover.