A total of 200 cattle of different ages, sexes, and breeds, suffering from respiratory symptoms, including 10 apparently healthy cattle, were examined clinically and bacteriologically for the isolation and identification of Histophilus somni. Enzyme-Linked Immunosorbent Assay (ELISA) was used to determine the levels of Bovine Interferon gamma (IFN-γ), Bovine Interleukin-4 (IL-4), and Immunoglobulin E (IgE) in the sera of the studied animals. Conventional bacteriological testing revealed that 25% (50/200) of the nasal swabs tested positive for H. somni. After culturing, the 16S rDNA and H. somni-specific PCR, gene sequencing, and phylogenetic analysis identified that 70% (35/50) of the isolates were confirmed to belong to Histophilus somni, with one isolate submitted to NCBI GenBank, receiving accession number OR100605. The seropositivity against H. somni LPS was estimated by an indirect ELISA test. The results showed that 35 (70%) of the cattle suffering from respiratory symptoms were seropositive for H. somni LPS. The LPS-specific IgE level, when compared between cattle with negative H. somni molecular results (0.429 ± 0.0139) and those with positive molecular results (0.733 ± 0.0227), showed a statistically significant (p < 0.05) increase in the mean Optical Density (OD) values. The association of IFN-γ and IL-4 with LPS-specific IgE antibodies was determined by indirect ELISA. The results indicated a significant (p < 0.05) increase in the mean IL-4 concentration in the sera of LPS-specific IgE seropositive cattle (200.151 ± 70.905) compared to seronegative animals (118.626 ± 27.642), with no statistically significant association (p > 0.05) between seropositivity and IFN-γ concentration. The results of this study suggest that H. somni LPS may induce a hypersensitized state in cattle. Additionally, this study suggests that Iraqi cattle may have elevated IgE levels against H. somni LPS.