This investigation aims to demonstrate the effects of hydrophobic tails on the affinity and relevant flotation response of sulfonate-based collectors for fluorite. For this purpose, a series of alkyl sulfonates with different hydrophobic tails, namely sodium decanesulfonate (C10), sodium dodecylsulfate (C12), sodium hexadecanesulfonate (C16), and sodium dodecylbenzenesulfonate (C12B) were applied. The flotation tests showed that C12 and C12B had a better collecting performance than C10 and C16 at pH < 10, and the flotation recovery of fluorite was higher when adopting C12B as a collector compared with C12 with a strong base. The adsorption behaviors of collectors on the fluorite surface were studied through zeta potential, Fourier transform infrared (FTIR), and X-ray photoelectron spectroscopy (XPS) analyses. It was found that the affinity of alkyl sulfonates for fluorite was enhanced with the increase of the alkyl chain length from C10 to C16. The existence of phenyl in the hydrophobic tail of sulfonates could improve its activity for fluorite by reducing its surface tension. The abnormal phenomenon C16 with a high affinity for fluorite had a low collecting performance for fluorite mainly due to its overlong alkyl chain, resulting in low solubility in pulp, which restrained its interaction with fluorite. We concluded that C12B was the most applicable collector for fluorite among these reagents due to its high activity, high solubility, and low cost, which was further substantiated by calculating their molecular frontier orbital energy.