Current challenges in froth flotation are the presence of complex gangues and the use of low quality waters, such as seawater. In this scenario, the recovery of molybdenum minerals is difficult, mainly due to the hydrophobic faces’ physicochemical changes. In the present study, the natural floatability of pure molybdenite was analyzed by using microflotation assays, and hydrophobicity was measured by performing contact-angle measurements. The impact of two clays, kaolin (nonswelling) and Na-montmorillonite (swelling), was studied. The behavior in freshwater and seawater at pH 8 was compared, considering the current condition of the Cu/Mo mining industries, which use seawater in their operations. The presence of clays lowered the natural floatability of molybdenite precisely because they adhere to the surface and reduce its contact angle. However, the intensity with which they cause this phenomenon depends on the type of water and clay. Kaolin strongly adheres to the valuable mineral in both freshwater and seawater. For its part, Na-montmorillonite does it with greater intensity in a saline medium, but in freshwater, a high concentration of phyllosilicate is required to reduce the hydrophobicity of molybdenite. The clays’ adherence was validated by scanning electron microscopy (SEM) analysis.