Natural and artificial systems containing water resources that have different salinities can be used to generate salinity-gradient energy (SGE). In this paper, the feasibility of implementing SGE in hypersaline coastal lagoons is addressed, taking the coastal lagoon La Carbonera in Yucatan, Mexico, as an exemplary case. A realistic approach to the exploitation conditions and potential that could occur in a SGE plant in these ecosystems is presented. We first analyzed the variability of salinity and temperature in the three characteristic zones of the coastal lagoon and the correlation of these variables with atmospheric forcing. This was done using 1 year records of in situ measurements. Then the theoretical potential for SGE and the intra-annual variability of that potential were assessed considering the three possible harvesting configurations of mixing among fresh, sea, and hypersaline water. Results show that the thermohaline structure may vary significantly for the three locations at different time scales (diurnal to seasonal) depending on the tides, winds, air temperature, atmospheric pressure, and solar radiation. That suggests that the highest annual energy yield would be obtained from alternating throughout the year among the mixing configurations, depending on the specific seasonal thermohaline structure of the lagoon.