Bovine respiratory disease (BRD) is economically significant, and influenza D virus (IDV) is commonly identified in cattle with BRD. Mannheimia haemolytica (MHA) is an opportunistic bacterial contributor to BRD; surveillance data suggest that MHA and IDV co-infection occurs in cattle. The objective of this study was to evaluate the synergistic pathogenesis in cattle co-infected with IDV and MHA. Sixteen dairy calves were randomly assigned to four groups of four calves. The IDV?+?MHA?+?group received D/bovine/C00046?N/Mississippi/2014 (D/46?N) intranasally at 0 days post-inoculation (DPI) and Mannheimia haemolytica D153 (MHA D153) intratracheally at 5 DPI. The IDV?+?MHA- group received only D/46?N at 0 DPI; the IDV-MHA?+?group received only MHA D153 at 5 DPI; and the IDV-MHA- group received neither agent. Clinical scores were calculated twice daily. At 10 DPI, IDV?+?MHA+, IDV-MHA+, and IDV-MHA- calves were euthanized and evaluated for pathologic lesions. The IDV?+?groups seroconverted to IDV by 10 DPI. Clinical scores were higher in IDV?+?groups than IDV- groups on 2-5 DPI (p?=? 0.001). After MHA challenge on 5 DPI, clinical scores (6-10 DPI) were slightly lower in IDV+MHA+ group than IDV-MHA+ group (p?