Neuraxial anesthesia may improve perioperative outcomes when compared to general anesthesia; however, this is controversial. We performed a systematic review and meta-analysis using randomized controlled trials and population-based observational studies identified in MEDLINE, PubMed, and EMBASE from 2010 to May 31, 2016. Studies were included for adult patients undergoing major surgery of the trunk and lower extremity that reported: 30-day mortality (primary outcome), cardiopulmonary morbidity, surgical site infection, thromboembolic events, blood transfusion, and resource use. Perioperative outcomes were compared with general anesthesia for the following subgroups: combined neuraxial-general anesthesia and neuraxial anesthesia alone. Odds ratios (ORs) and 99% confidence intervals (CIs) were calculated to identify the impact of anesthetic technique on outcomes. Twenty-seven observational studies and 11 randomized control trials were identified. This analysis comprises 1,082,965 records from observational studies or databases and 1134 patients from randomized controlled trials. There was no difference in 30-day mortality identified when combined neuraxial-general anesthesia was compared with general anesthesia (OR 0.88; 99% CI, 0.77–1.01), or when neuraxial anesthesia was compared with general anesthesia (OR 0.98; 99% CI, 0.92–1.04). When combined neuraxial-general anesthesia was compared with general anesthesia, combined neuraxial-general anesthesia was associated with a reduced odds of pulmonary complication (OR 0.84; 99% CI, 0.79–0.88), surgical site infection (OR 0.93; 99% CI, 0.88–0.98), blood transfusion (OR 0.90; 99% CI, 0.87–0.93), thromboembolic events (OR 0.84; 99% CI, 0.73–0.98), length of stay (mean difference −0.16 days; 99% CI, −0.17 to −0.15), and intensive care unit admission (OR 0.77; 99% CI, 0.73–0.81). For the combined neuraxial-general anesthesia subgroup, there were increased odds of myocardial infarction (OR 1.18; 99% CI, 1.01–1.37). There was no difference identified in the odds of pneumonia (OR 0.94; 99% CI, 0.87–1.02) or cardiac complications (OR 1.04; 99% CI, 1.00–1.09) for the combined neuraxial-general anesthesia subgroup. When neuraxial anesthesia was compared to general anesthesia, there was a decreased odds of any pulmonary complication (OR 0.38; 99% CI, 0.36–0.40), surgical site infection (OR 0.76; 99% CI, 0.71–0.82), blood transfusion (OR 0.85; 99% CI, 0.82–0.88), thromboembolic events (OR 0.79; 99% CI, 0.68–0.91), length of stay (mean difference −0.29 days; 99% CI, −0.29 to −0.28), and intensive care unit admission (OR 0.50; 99% CI, 0.48–0.53). There was no difference in the odds of cardiac complications (OR 0.99; 99% CI, 0.94–1.03), myocardial infarction (OR 0.91; 99% CI, 0.81–1.02), or pneumonia (OR 0.92; 99% CI, 0.84–1.01). Randomized control trials revealed no difference in requirement for blood transfusion (RR 1.05; 99% CI, 0.65–1.71) and a decreased length of stay (mean difference −0.15 days; 99% CI, −0.27 to −0.04). Neuraxial anesthesia when combined with general anesthesia or when used alone was not associated with decreased 30-day mortality. Neuraxial anesthesia may improve pulmonary outcomes and reduce resource use when compared with general anesthesia. However, because observational studies were included in this analysis, there is a risk of residual confounding and therefore these results should be interpreted with caution.