In the African buffalo (Syncerus caffer) population of the Kruger National Park (South Africa) a primary sex-ratio distorter and a primary sex-ratio suppressor have been shown to occur on the Y chromosome. A subsequent autosomal microsatellite study indicated that two types of deleterious alleles with a negative effect on male body condition, but a positive effect on relative fitness when averaged across sexes and generations, occur genome-wide and at high frequencies in the same population. One type negatively affects body condition of both sexes, while the other acts antagonistically: it negatively affects male but positively affects female body condition. Here we show that high frequencies of male-deleterious alleles are attributable to Y-chromosomal distorter-suppressor pair activity and that these alleles are suppressed in individuals born after three dry pre-birth years, likely through epigenetic modification. Epigenetic suppression was indicated by statistical interactions between pre-birth rainfall, a proxy for parental body condition, and the phenotypic effect of homozygosity/heterozygosity status of microsatellites linked to male-deleterious alleles, while a role for the Y-chromosomal distorter-suppressor pair was indicated by between-sex genetic differences among pre-dispersal calves. We argue that suppression of male-deleterious alleles results in negative frequency-dependent selection of the Y distorter and suppressor; a prerequisite for a stable polymorphism of the Y distorter-suppressor pair. The Y distorter seems to be responsible for positive selection of male-deleterious alleles during resource-rich periods and the Y suppressor for positive selection of these alleles during resource-poor periods. Male-deleterious alleles were also associated with susceptibility to bovine tuberculosis, indicating that Kruger buffalo are sensitive to stressors such as diseases and droughts. We anticipate that future genetic studies on African buffalo will provide important new insights into gene fitness and epigenetic modification in the context of sex-ratio distortion and infectious disease dynamics.