We reported herein the synthesis, antifungal activity, docking and in silico ADME prediction studies of four novel series of sulfones 6a–f, 8a–c, 10a–f and 12a–c. All the newly synthesized sulfones were tested against four strains of Candida (including fluconazole-resistant Candida), two strains of Aspergillus, two dermatophytic fungi (Trichophytons mentagrophyte and Microsporum canis) and Syncephalastrum sp. with fluconazole as a reference drug. In general, compounds 8a and 10b showed selective and potent anticandidal activity (MIC: 0.19–0.81 µM) relative to fluconazole (MIC = 1.00 µM). Furthermore, 10e and 12a elicited a remarkable and selective antifungal activity against Aspergillus sp. and the dermatophytic fungi (MIC: 0.16–0.79 µM) relative to fluconazole (MIC: 2–2.6 µM). Moreover, the docking results of the sulfones 6a, 8a, 10a and 10b at the active site of CYT P450 14α-sterol demethylase showed a comparable binding interaction (interaction Energy = −34.87 to −42.43 kcal/mol) with that of fluconazole (IE = −40.37 kcal/mol).