The characterization and quantification of risk in port activities are essential to determine the main factors that may cause incidents and to establish risk mitigation strategies to improve the safety and operability of ports. This study presents a novel methodology to analyze the hydrometeorological risk of navigation in fairways and port activities, which is applied to the study case of the 22-km section of the lower Magdalena River, near the port of Barranquilla (Colombia). The methodology is based on probabilistic models of dominant hydrometeorological variables (e.g., water depth, flow velocity, wind magnitude, and wave height) identified via hazard and operative (HAZOP) studies. It allowed for quantifying likelihood and vulnerability levels obtained by empirical functions representing monthly spatio-temporal risk. It can be applied at any stage of fairway design and is highly replicable at other geographical conditions. The results for the study area show that the main risk factors for the reference vessel (i.e., SUPRAMAX) are the wave height and the fairway depth, which on up to 15% of the cases restrict navigation and induce deviations and economic losses to the port authority.