An amorphous fiber-based solid dispersion of chlorzoxazone was prepared for the first time by employing centrifugal spinning, using polyvinylpyrrolidone as the fiber-forming polymer. After optimization of the spinning parameters, the obtained fibers were characterized using a set of analytical techniques, both in a solid- and solution-state. Morphological characterization revealed a slightly aligned, defect-free fibrous structure with an average fiber diameter of d = 3.07 ± 1.32 μm. The differential scanning calorimetric results indicated a crystalline-to-amorphous transition of the active substance during the centrifugal spinning process, while gas chromatographic determinations revealed a residual ethanol content of 0.42 ± 0.04%. UV spectroscopy indicated the incorporation of chlorzoxazone in the fibrous structures, with an average active substance content of 15.91 ± 0.36 w/w%. During small-volume dissolution studies, the prepared fiber mats presented immediate disintegration upon contact with the dissolution media, followed by rapid dissolution of the active substance, with 84.8% dissolved at 1 min and 93.7% at 3 min, outperforming the micronized, pure chlorzoxazone. The obtained results indicate that centrifugal spinning is a low-cost, high-yield, viable alternative to the currently used methods to prepare fiber-based amorphous solid dispersions of poorly soluble drugs. The prepared chlorzoxazone-loaded microfibers could be used as a buccal dosage form for the systematic delivery of chlorzoxazone and could potentially lead to a rapid onset of action and longer efficacy of the muscle relaxant drug.