Closantel is widely used in the management of parasitic infestation in livestock, but is contraindicated in humans due to its high toxic to human retina. Thus, development of a fast and selective method for the detection of closantel residues in animal products is highly needed yet still challenging. In the present study, we report a supramolecular fluorescent sensor for closantel detection through a two-step screening process. The fluorescent sensor can detect closantel with a fast response (<10 s), high sensitivity, and high selectivity. The limit of detection is 0.29 ppm, which is much lower than the maximum residue level set by government. Moreover, the applicability of this sensor has been demonstrated in commercial drugs tablets, injection fluids, and real edible animal products (muscle, kidney, and liver). This work provides the first fluorescence analytical tool for accurate and selective determination of closantel, and may inspire more sensor design for food analysis.