The emergence of avian reovirus variant strains has caused negative effects in the poultry industry worldwide. Regardless of the efforts in molecular characterization and classification of these variants, information about the pathogenicity, transmissibility, and immunosuppression in chickens is limited. The genomes of two variant strains (A and B) and a classic S1133 strain (C) belonging to the same sigma C genotype 1 were compared. Additionally, these strains were used in a challenge experiment to evaluate inoculated and indirectly exposed specific-pathogen-free chickens. The whole-genome sequence analysis of the three strains revealed nucleotide identity differences in the L3, M2, and S1 genes. Strains A and B also showed homology differences in the S4 gene, despite having high homologies in all other genes. The in vivo challenge experiments showed that, whereas variant A induced high viral loads in tendons, hearts, and duodena of inoculated chickens, variant B induced high viral loads in indirectly exposed chickens. Likewise, histopathology reflected differences in the pathologic effects induced by these strains. For instance, the B and C strains induced more severe microscopic lesions compared with the A strain. Lymphoid depletion was more severe in bursas than in thymi, and inoculated birds were more affected than exposed birds. In conclusion, different pathologic outcomes in chickens were observed depending on the strain and transmission route. This study provides insights onto the relationship between pathogenicity and genomic composition of avian reoviruses.