Mangroves occur in coastal areas and are therefore vulnerable to anthropogenic disturbance and exhibit high rates of deforestation. Mexico is among the countries with the highest degree of mangrove deforestation in America; however, precise data on national mangrove coverage in Mexico is incomplete, making it impossible to accurately ascertain the rate of mangrove loss over time. Precise information is necessary to assess changes at local and regional scales to detect the magnitude, trends, and drivers of the transformation. This study aimed to estimate the loss of mangrove cover in the area of Mahahual-Xcalak (Quintana Roo, Mexico) between 1995 and 2007, to calculate the annual deforestation rate and to identify the drivers of deforestation. Landsat TM and ETM+ images from 1995 and 2007 were used to estimate the loss of mangrove cover using a multitemporal analysis. Semi-structured interviews with local residents of Mahahual and Xcalak were undertaken to identify and validate the drivers of deforestation. The image analysis for the 12-year period showed that 1070 ha of mangrove forest have been lost, with an annual deforestation rate of 0.85%—a relatively high value compared with other mangrove regions in Mexico. The main factor that has triggered the reduction of mangrove coverage is the expansion of anthropogenic land uses (e.g., settlements and roads). This study concludes that conservation and rehabilitation programs need to be implemented so that the Mahahual-Xcalak mangrove environment can continue to provide key ecosystem services.