(1) Background: The technological advances achieved with minimally-invasive surgery have enabled procedures to be undertaken in outpatient settings, and there has been growing acceptance of performing minimally-invasive transforaminal interbody fusion (TLIF) in the ambulatory surgery center (ASC). The purposeof this study was to determine the comparative 30 day safety profile for patients treated with TLIF in the ASC versus the hospital setting. (2) Methods: This multi-center study retrospectively collected baseline characteristics, perioperative variables, and 30 day postoperative safety outcomes for patients having a TLIF using the VariLift^®-LX expandable lumbar interbody fusion device. Outcomes were compared between patients undergoing TLIF in the ASC (n = 53) versus in the hospital (n = 114). (3) Results: Patients treated in-hospital were significantly older, frailer and more likely to have had previous spinal surgery than ASC patients. Preoperative back and leg pain scores were similar between study groups (median, 7). ASC patients had almost exclusively one-level procedures (98%) vs. 20% of hospital procedures involving two-levels (p = 0.004). Most procedures (>90%) employed a stand-alone device. The median length of stay for hospital patients was five times greater than for ASC patients (1.4 days vs. 0.3 days, p = 0.001). Emergency department visits, re-admissions and reoperations were rare whether the patients were managed in the traditional hospital setting or the ASC. (4) Conclusions: There were equivalent 30 day postoperative safety profiles for patients undergoing a minimally-invasive TLIF irrespective of surgical setting. For appropriately selected surgical candidates, the ASC offers a viable and attractive option for their TLIF procedure with the advantage of same-day discharge and at-home recovery.