Background Patients undergoing lower limb revascularization surgery for peripheral artery disease (PAD) have a high risk of perioperative morbidity and mortality and often have long hospital stays. Use of neuraxial or regional anesthesia instead of general anesthesia may represent one approach to improving outcomes and reducing resource use among these patients. Objective The aim is to conduct a systematic review and meta-analysis to determine whether receipt of neuraxial or regional anesthesia instead of general anesthesia in adults undergoing lower limb revascularization surgery for PAD results in improved health outcomes and costs and a shorter length of hospitalization. Methods We will search electronic bibliographic databases (MEDLINE, EMBASE, the seven databases in Evidence-Based Medicine Reviews, medRxiv, bioRxiv, and Google Scholar), review papers identified during the search, and included article bibliographies. We will include randomized and nonrandomized studies comparing the use of neuraxial or regional anesthesia instead of general anesthesia in adults undergoing lower limb revascularization surgery for PAD. Two investigators will independently evaluate the risk of bias. The primary outcome will be short-term (in-hospital or 30-day) mortality. Secondary outcomes will include longer-term mortality; major adverse cardiovascular, pulmonary, renal, and limb events; delirium; deep vein thrombosis or pulmonary embolism; neuraxial or regional anesthesia–related complications; graft-related outcomes; length of operation and hospital stay; costs; and patient-reported or functional outcomes. We will calculate summary odds ratios (ORs) and standardized mean differences (SMDs) using random-effects models. Heterogeneity will be explored using stratified meta-analyses and meta-regression. We will assess for publication bias using the Begg and Egger tests and use the trim-and-fill method to estimate the potential influence of this bias on summary estimates. Finally, we will use Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology to make an overall rating of the quality of evidence in our effect estimates. Results The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO). We executed the peer-reviewed search strategy on March 2, 2021. We completed the review of titles and abstracts on July 30, 2021, and plan to complete the review of full-text papers by September 30, 2021. We will complete full-text study data extraction and the risk-of-bias assessment by November 15, 2021, and conduct qualitative and then quantitative data synthesis and GRADE assessment of results by January 1, 2022, before drafting the manuscript. We anticipate that we will be able to submit the manuscript for peer review by the end of February 2022. Conclusions This study will synthesize existing evidence regarding whether receipt of neuraxial or regional anesthesia instead of general anesthesia in adults undergoing lower limb revascularization surgery for PAD results in improved health outcomes, graft patency, and costs and a shorter length of hospital stay. Study results will be used to inform practice and future research, including creation of a pilot and then multicenter randomized controlled trial. Trial Registration Prospero CRD42021237060; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=237060 International Registered Report Identifier (IRRID) PRR1-10.2196/32170