Marijuana and opioids are commonly used illicit drugs in the United States and their use continues to rise. Cannabis use disorder (CUD) and Opioid use disorder (OUD) are associated with adverse effects on public health and postoperative outcomes. However, their impact on vascular surgery, specifically infrainguinal bypass repair (IIB). is not well described in the literature. Therefore, our study aimed to assess perioperative outcomes in patients with CUD and OUD who underwent IIB. A retrospective analysis of the National Inpatient Sample database for the years 2005 to 2018 was performed. Using the International Classification of Diseases Clinical Modification, Ninth and Tenth revisions, patients who were diagnosed with peripheral artery disease and underwent IIB repair.were identified. Our primary outcome was the comparison of rates of in-hospital complications between the groups, and the secondary outcomes included analysis of total hospital charges and length of stay. A 1:1 propensity score matching (PSM) CUD and OUD patients to their control groups without the disease was conducted using the nearest-neighbor method. The matching was based on select patient demographics and comorbidities included in our analyses. A total of 190,794 patients were identified: 972 patients with CUD and 682 patients with OUD. In the matched cohorts, patients with a diagnosis of CUD had a higher incidence of in-hospital cardiac complications (adjusted Odds Ratio [aOR], 1.76; 95% Confidence Interval [CI], 0.99-3.12) and acute kidney injury (AKI) (aOR, 1.51; CI, 1.09-2.08). Additionally, total hospital charges and mean length of stay were higher in the CUD group (P < 0.001). Those with OUD had a higher incidence of postoperative respiratory complications (aOR, 1.92; CI, 1.23-2.99), sepsis (aOR, 2.39; CI, 1.32-4.34), infection (aOR, 3.55; CI, 1.16-10.84), AKI (aOR, 2.11; CI,1.47-3.04), major amputations (aOR, 1.69; CI, 1.07-2.69), along with higher total charges and mean length of stay (P < 0.001). Both CUD and OUD have increased incidence of postoperative complications following IIB. The OUD group had generally worse outcomes compared to patients with CUD. Both were associated with a substantial increase in total hospital charges and length of hospital stay. A further prospective study is warranted to provide better insight on the effects of substance use disorders on the procedure's short- and long-term outcomes.