The Mekong Delta produces 55% of Vietnam’s rice (Oryza sativa L.) through double or triple cropping each year. It accounts for a large proportion of Vietnam’s anthropogenic methane (CH4) emissions. Alternate wetting and drying (AWD) is a paddy water management practice recognized as a promising CH4 mitigation option and may increase rice yield. However, AWD may also increase nitrous oxide (N2O) emissions and its implementation is troublesome for farmers. Therefore, a simplified form of AWD (referred to here as “multiple drainage,” MD) is often adopted in An Giang Province, where full dike systems are prevailing, in the Mekong Delta. To evaluate the effects of MD on rice yield and emissions of CH4 and N2O in An Giang Province, we carried out 2-year field experiments at three remote sites each surrounded by the dike systems. We compared MD and continuous flooding (CF) at each site under conventional agronomic practices through six consecutive rice growing seasons. Fluxes of CH4 and N2O were measured by a closed chamber method. MD was achieved with varying degrees of success at each site, except during heavy rainfall events. Rice yield was significantly (P < 0.05) increased (by 22%) in MD plots relative to CF plots. Seasonal total CH4 emissions were significantly reduced (by 35%) in MD plots, but no difference was found in N2O emissions. These results indicate that MD, if adequately implemented, can increase rice yield and decrease CH4 emissions in paddy fields in An Giang Province, Vietnam.