The purpose of this study was to compare outcomes between patients undergoing same-day discharge (SDD) total knee arthroplasty (TKA) at an ambulatory surgery center (ASC) versus a tertiary care university hospital setting. A single tertiary academic center's institutional database was reviewed for patients that underwent primary TKA and were discharged the same day from August 2021 to January 2024. Patients who did not have at least one year of follow-up were excluded. Patient demographics, comorbidities, patient-reported outcome measures (PROMs), emergency department (ED) visits, admissions, reoperations, and revisions were collected. Patients were stratified by the location of their surgery: ASC versus hospital. Specific criteria had to be met prior to surgery at the ASC, and the final decision regarding the location of surgery was made via shared decision-making between the patient and their surgeon. Patients who did not meet ASC criteria underwent TKA at the main hospital. Univariable analyses were used to compare groups, and multivariable logistic regression was used to determine if surgical location was a significant factor. Of the 449 TKAs meeting inclusion criteria, 63.3% (284) were performed at the ASC and 36.7% (165) at the university hospital at a mean follow-up of 1.51 years (range, 1.00 to 2.40). Of those 165 whose surgery was done at the hospital, 93.9% met at least one ASC exclusion criteria. Patients whose TKA was done at the hospital had significantly higher weight (P = 0.003), body mass index (BMI) (P < 0.001), Elixhauser comorbidity index (ECI) (P < 0.001), proportion of patients who had an American Society of Anesthesiologists (ASA) classification of 3 (P = 0.023), and proportion of patients who required general anesthesia (P < 0.001). Additionally, patients whose TKA was done at the hospital had higher preoperative patient-reported outcome measurement information system (PROMIS) pain interference (PI) (62.0 [59.0, 66.0] versus 63.0 [61.8, 67.0]; P = 0.006), and lower physical function (PF) (39.0 [36.0, 43.0] versus 38.0 [34.0, 41.0]; P = 0.001). At 1 year, however, patients in both groups had similar PROMIS PI (53.0 [49.0, 59.0] versus 54.0 [44.0, 59.0]; P = 0.785) and PROMIS PF (47.0 [42.0, 51.0] versus 47.0 [41.0, 50.0]; P = 0422) scores as well as similar rates of achieving minimum clinically important difference (MCID) for PROMIS PI (64.4 versus 71.4%; P = 0.336) and PROMIS PF (60.5 versus 71.4%; P = 0.124). They also had a similar number of ED visits and admissions at 30 and 90 days, as well as similar reoperation-free (92.0 versus 93.3%; P = 0.79) and revision-free (95.5 versus 99.4%; P = 0.59) survival at 2 years. Although ASCs have strict patient criteria for SDD TKA, complex patients at a tertiary university hospital can be sent home the same day with equivalent outcomes. Therefore, unhealthier patients can safely achieve SDD without compromising outcomes if done in the appropriate setting.