The resistance risk and mechanisms of propiconazole in Rhizoctonia solani remain unclear. In this study, the sensitivity of 159 R. solani isolates to propiconazole was determined, and the EC50 value was 0.2286 μg/mL. Nineteen propiconazole-resistant mutants of R. solani were obtained through fungicide adaptation, and the compound fitness indexes of these propiconazole-resistant mutants were lower than those of their parental isolates. Cross-resistance analysis revealed that there was no cross-resistance between propiconazole and other fungicides, apart from prochloraz. Although no point mutations occurred in the RsCYP51 gene or its promoter regions, the expression levels of RsCYP51 and efflux transporter genes increased substantially in the propiconazole-resistant mutants. Furthermore, a 1:1 synergistic combination of propiconazole and kresoxim-methyl (SCpk(1:1)) could simultaneously cause more severe damage to both cell membrane integrity and mitochondrial function. Field trials demonstrated that SCpk(1:1) achieved over 86% control efficacy against rice sheath blight applied at 120 g a.i./ha.