Nanobubbles have recently been proposed as a promising technology to enhance mineral flotation; however, their behavior in real ores with complex mineralogy remains poorly understood. This study evaluates the effect of nanobubbles on the flotation of copper sulfide ores from Chilean porphyry deposits with contrasting clay contents. Two representative samples were analyzed: a low-clay-content ore (M1) and a high-clay-content ore (M2). Flotation tests were carried out in a 2.7 L forced-air cell, using kinetic experiments with and without nanobubbles and frother addition. The mineralogical composition was characterized by XRD and QEMSCAN, while SEM-EDS was used to analyze surface morphology and particle associations. The results showed that nanobubbles improved copper and molybdenum recoveries in M1 up to 7.5 and 20%, respectively, increasing both kinetics and final recovery, which was supported by SEM observations of clean surfaces and compact agglomerates. In contrast, in M2 the use of nanobubbles decreased flotation efficiency due to enhanced slime coating and the formation of non-selective agglomerates, which reduced the hydrophobicity of sulfide surfaces. Overall, this study demonstrates that the efficiency of nanobubbles strongly depends on ore mineralogy, offering advantages in clean systems but limitations in clay-rich ores, and highlights the need for mineral-specific strategies for their successful industrial application.