Bovine TB is a disease of high economic and public health importance particularly in resource poor countries. Many aspects of pathogenesis of bovine TB in cattle have not been well understood. We carried out an investigation on 337 Ethiopian cattle with characteristic TB-like lesions to describe severity of pathology and factors associated with it. Severity of pathology was determined based upon gross lesion characteristics, distribution and presence/absence of viable mycobacteria. Molecular speciation of mycobacteria was performed using Gene-Probe's Accu-Probe method. Mycobacterium bovis was identified by genomic deletion analysis and spoligotyping. Data were analysed using descriptive statistics and regression model. The results showed that TB-like lesions and M. bovis were more frequently observed in lungs and respiratory lymph nodes. Mammary lesions yielded significant proportion of M. bovis upon culturing. Intestinal lesions were the second most frequently encountered pathology; upon culturing, however, the tissue specimens yielded the lowest proportion of M. bovis isolates. Sex, breed and management system were found to significantly affect TB manifestation. Female (β ± SE = 4.1 ± 1.0; P = 0.00) and exotic breed (β ± SE = 1.7 ± 0.9; P = 0.045) were at a relatively higher risk of developing severe tuberculosis. TB pathology was more severe in cattle raised under large-scale farming (β ± SE = 2.3 ± 0.5; P = 0.00). The fact that severe tuberculosis is linked to high degree of disease transmission potential warrants implementation of proper disease surveillance programs in large-scale farms. Isolation of M. bovis from mammary and muscle tissues implies a potential threat of zoonotic transmission, where raw milk and raw beef constitute a customary dietary regimen in Ethiopia.