In order to implement osmotic power as a renewable energy source it is necessary to take into account the site-specific characteristics of any river mouth location where a project is proposed. This includes the salinity structure, inter- and intra-annual flow variations, ecological and social restrictions of the flow extraction, among others. Using the case of a location with suitable conditions for osmotic power, the León River mouth at the Colombian Caribbean Coast is analyzed in detail. A discharge analysis is undertaken to determine the appropriate size of an osmotic power plant by studying the relationships of the flow extraction with the installed capacity, load factor and yearly generation of the power plant. Furthermore, hydrological and ecological characteristics of the river are taken into account. Once the design flow is determined, the impact of the flow extraction on the salinity structure is analyzed for different climatic scenarios defined by the ENSO phases. The developed methodology can be taken as a basis to assess the osmotic power potential of other rivers on a worldwide level.