The present paper demonstrates that inundation levels in the Mekong Delta’s largest city, Can Tho, are predominantly determined by ocean tides, sea-level rise, and land subsidence. Our analysis of inundation patterns projects that the duration of inundation at an important road in the city will continue to rise from the current total of 72 inundated days per year to 270 days by 2030 and 365 days by 2050. This is attributed to the combined influence of sea-level rise and land subsidence, which causes relative water level rises at a rate of 22.3 mm·yr−1. People in the Mekong Delta have traditionally lived with floods, and thus there is certain resilience among residents in coping with small floods. At present, daily maximum inundation depth, which is generally shallower than 10 cm on the road, seems to be still manageable; however, our analysis indicates that this will start drastically increasing in the coming decades and reach an average depth of 70 cm by 2050. Effective and well-planned actions to mitigate the effects of land subsidence and sea-level rise are urgently required, otherwise, local inhabitants will encounter an unmanageable increase in inundation depth and duration in the coming decades. This study, which considers both sea-level rise and land subsidence, suggests that inundation depth and duration are projected to rise much faster than those indicated by previous studies, which only consider sea-level rise.