The differential efficacy of lipophilic and hydrophilic β-blockers on clinical outcomes has not been investigated. We sought to compare the effects of lipophilic and hydrophilic β-blockers on mortality and cardiovascular outcomes by conducting a comprehensive systematic review and network meta-analysis. MEDLINE/PubMed, EMBASE, and the Cochrane Database were searched for all dates to January 5, 2015, for randomized trials with comparisons between all β-blockers or between β-blockers and other antihypertensive agents. Mortality and cardiovascular outcomes were also reported. Characteristics of each study and associated clinical outcomes were extracted, including all-cause mortality, coronary heart disease, stroke, and cardiovascular death. Thirteen trials with 90,935 participants were included, focusing on lipophilic β-blockers (metoprolol, propranolol, and oxprenolol) and a hydrophilic β-blocker (atenolol). In this review, lipophilic β-blockers showed a significant reduction for the risk of cardiovascular mortality (odds ratio [OR] 0.72, 95% confidence interval [CI; 0.54-0.97]) compared with hydrophilic β-blocker, and lipophilic β-blockers showed decreased trend for the risk of all-cause mortality (OR 0.86, 95% CI [0.72-1.03]) and coronary heart disease (OR 0.88, 95% CI [0.64-1.23]). When the risk of stroke was evaluated using age stratification, lipophilic β-blockers showed a significant reduction in the risk of stroke (OR 0.63, 95% CI [0.41-0.99]) compared with hydrophilic β-blocker in patients aged <65 years.