Fusarium graminearum exhibited natural resistance to a majority of succinate dehydrogenase inhibitor fungicides (SDHIs) and the molecular mechanisms responsible for the natural resistance were still unknown. Succinate dehydrogenase subunit C (SdhC) is an essential gene for maintaining succinate-ubiquinone oxidoreductase (SQR) function in fungi. In F. graminearum, a paralog of FgSdhC named as FgSdhC was identified. Based on RNA-Seq and qRT-PCR assay, we found that the expression level of FgSdhC was very low but upregulated by SDHIs treatment. Based on reverse genetics, we demonstrated that FgSdhC was an inessential gene in normal growth but was sufficient for maintaining SQR function and conferred natural resistance or reduced sensitivity toward SDHIs. Additionally, we found that the standard F. graminearum isolate PH-1 had high sensitivity to a majority of SDHIs. A single nucleotide variation (C to T) in the FgSdhC of isolate PH-1, resulting in a premature termination codon (TAA) replacing the fourth amino acid glutamine (Q), led to the failure of FgSdhC to perform functions of conferring nature resistance. These results established that a dispensable paralogous gene determined SDHIs resistance in natural populations of F. graminearum.