As vaccine resources were distributed unevenly worldwide, sometimes there might have been shortages or delays in vaccine supply; therefore, considering the use of heterogeneous booster doses for Coronavirus disease 2019 (COVID-19) might be an alternative strategy. Therefore, we aimed to review the data available to evaluate and compare the effectiveness and safety of heterologous booster doses with homologous booster doses for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. We searched relevant studies up to 27 April 2022. Random-effects inverse variance models were used to evaluate the vaccine effectiveness (VE) and its 95% confidence interval (CI) of COVID-19 outcomes and odds ratio (OR) and its CI of safety events. The Newcastle-Ottawa quality assessment scale and Cochrane Collaboration's tool were used to assess the quality of the included cohort studies. A total of 23 studies involving 1,726,506 inoculation cases of homologous booster dose and 5,343,580 inoculation cases of heterologous booster dose was included. The VE of heterologous booster for the prevention of SARS-CoV-2 infection (VEheterologous = 96.10%, VEhomologous = 84.00%), symptomatic COVID-19 (VEheterologous = 56.80%, VEhomologous = 17.30%), and COVID-19-related hospital admissions (VEheterologous = 97.40%, VEhomologous = 93.20%) was higher than homologous booster. Compared with homologous booster group, there was a higher risk of fever (OR = 1.930, 95% CI, 1.199-3.107), myalgia (OR = 1.825, 95% CI, 1.079-3.089), and malaise or fatigue (OR = 1.745, 95% CI, 1.047-2.906) within 7 days after boosting, and a higher risk of malaise or fatigue (OR = 4.140, 95% CI, 1.729-9.916) within 28 days after boosting in heterologous booster group. Compared with homologous booster group, geometric mean neutralizing titers (GMTs) of neutralizing antibody for different SARS-CoV-2 variants and response rate of antibody and gama interferon were higher in heterologous booster group. Our findings suggested that both homologous and heterologous COVID-19 booster doses had great effectiveness, immunogenicity, and acceptable safety, and a heterologous booster dose was more effective, which would help make appropriate public health decisions and reduce public hesitancy in vaccination.