(1) Background: The surgical procedure to create an arteriovenous fistula (AVF) can be performed in either an ambulatory or in-patient hospital setting, depending on the case's complexity, the anesthesia type used, and the patient's comorbidities. The main scope of this study is to assess the cost-effectiveness and clinical implications of surgically creating an AVF in both ambulatory and in-hospital settings. (2) Methods: We conducted a retrospective observational study, in which we initially enrolled all patients with end-stage kidney disease (ESKD) admitted to the Vascular Surgery Department, Emergency County Hospital of Targu Mures, Romania, to surgically create an AVF for dialysis, between January 2020 and December 2022. The primary endpoint of this study is to assess the cost-effectiveness of surgically creating an AVF in an ambulatory vs. in-hospital setting by comparing the costs required for the two types of admissions. Further, the 116 patients enrolled in this study were divided into two groups based on their preference for hospitalization: out-patients and in-patients. (3) Results: Regarding in-patient comorbidities, there was a higher prevalence of peripheral artery disease (PAD) (p = 0.006), malignancy (p = 0.020), and previous myocardial infarction (p = 0.012). In addition, active smoking (p = 0.006) and obesity (p = 0.018) were more frequent among these patients. Regarding the laboratory data, the in-patients had lower levels of white blood cells (WBC) (p = 0.004), neutrophils count (p = 0.025), lymphocytes (p = 0.034), and monocytes (p = 0.032), but there were no differences between the two groups regarding the systemic inflammatory biomarkers or the AVF type. Additionally, we did not register any difference regarding the outcomes: local complications (p = 0.588), maturation failure (p = 0.267), and primary patency (p = 0.834). In our subsequent analysis, we discovered no significant difference between the hospitalization type chosen by patients regarding AVF primary patency failure (p = 0.195). We found no significant association between the hospitalization type and the recorded outcomes (all ps > 0.05) in both multivariate linear regression and Cox proportional hazard analysis. (4) Conclusions: In conclusion, there are no significant differences in the clinical implications, short-term and long-term complications of AVF for out-patient and in-patient admissions. Additionally, we found no variation in the costs associated with laboratory tests and surgical supplies for an AVF creation. Therefore, it is safe to perform ambulatory AVFs, which can reduce the risk of hospital-acquired infections and provide greater comfort to the patient.