Sensitivity to azoxystrobin and kresoxim-methyl of 80 single-spore isolates of Magnaporthe oryzae was determined. The EC50 values for azoxystrobin and kresoxim-methyl in inhibiting mycelial growth of the 80 M. oryzae isolates were 0.006–0.056 and 0.024–0.287 μg mL−1, respectively. The EC50 values for azoxystrobin and kresoxim-methyl in inhibiting conidial germination of the M. oryzae populations were 0.004–0.051 and 0.012–0.105 μg mL−1, respectively. There was significant difference in sensitivity to azoxystrobin or kresoxim-methyl between the tested isolates representing differential sensitivity to carbendazim (MBC) and kitazin P (IBP); however, there was no correlation between this difference in sensitivity to azoxystrobin or kresoxim-methyl and sensitivity to MBC or IBP, indicating that there was no cross-resistance between azoxystrobin or kresoxim-methyl and MBC or IBP. In the protective and curative experiments, kresoxim-methyl exhibited higher protective and curative activity than azoxystrobin when applied at 150 and 250 μg mL−1 accordingly, while azoxystrobin exhibited stronger inhibitory activity against M. oryzae isolates than that of kresoxim-methyl in the in vitro test. The results of field experiments also suggested that both azoxystrobin and kresoxim-methyl at 187.5 g.a.i. ha−1 gave over 73% control efficacy in both sites, exhibiting excellent activity against rice blast. Taken together, azoxystrobin and kresoxim-methyl could be a good substitute for MBC or IBP for controlling rice blast in China, but should be carefully used as they were both at-risk.