The Fano resonance is a widespread wave scattering phenomenon associated with a peculiar asymmetric and ultrasharp line shape, which has found applications in a large variety of prominent optical devices. While its substantial sensitivity to geometrical and environmental changes makes it the cornerstone of efficient sensors, it also renders the practical realization of Fano-based systems extremely challenging. Here, we introduce the concept of topological Fano resonance, whose ultrasharp asymmetric line shape is guaranteed by design and protected against geometrical imperfections, yet remaining sensitive to external parameters. We report the experimental observation of such resonances in an acoustic system, and demonstrate their inherent robustness to geometrical disorder. Such topologically protected Fano resonances, which can also be found in microwave, optical, and plasmonic systems, open up exciting frontiers for the generation of various reliable wave-based devices including low-threshold lasers, perfect absorbers, ultrafast switches or modulators, and highly accurate interferometers, by circumventing the performance degradations caused by inadvertent fabrication flaws.