Introduction In this study we aimed to provide preliminary evidence on the safety and efficacy of the currently used ovine pasteurellosis vaccine in Ethiopia using clinical and pathological endpoints. Methods Twenty, conventionally reared, apparently healthy, seronegative male lambs, were randomly classified into two groups of 10 animals as “vaccinated-challenged” and ”unvaccinated-challenged controls”. The first group received 1 mL of the licensed Pasteurella multocida biotype A based vaccine subcutaneously while the second group received phosphate-buffered saline as a placebo. Following vaccination, lambs were monitored for one month for potential vaccine adverse reactions. Five weeks postvaccination, all lambs were immunosuppressed using dexamethasone, and intratracheally challenged with 5.2×10 9 CFU/mL live Mannheimia haemolytica A1 (clinical isolates). Then, all lambs were followed up for eight days for clinical examination and necropsied on the ninth day postchallenge for pathological investigation. Results There were no safety issues recorded during the study. In terms of clinical signs, lambs developed fever, depression, mucoid bilateral oculonasal discharge, coughing and sneezing regardless of their vaccination status. Fisher’s exact test between vaccination status and each clinical sign showed a statistically insignificant association ( p >0.05). The main pathological findings in both groups were pulmonary congestion, atelectasis, emphysema, and suppurative bronchopneumonia. Consolidation lung lesion score of +1 (5/10 of vaccinated, 6/10 of unvaccinated) and +2 (3/10 of vaccinated, 4/10 of unvaccinated) were recorded in a statistically indifferent manner among both vaccinated and nonvaccinated groups ( p >0.05). Discussion and Conclusion Collectively, the results suggested that the vaccine posed no safety concern and presumably lacks protective efficacy against local isolates. However, the study did not analyze antibody titer and their functionality using serum bactericidal assays. Further confirmatory studies could provide more evidence on the vaccine efficacy. Safety should further be assessed in a field setting involving a large number of animals to enable detection of rare vaccine adverse events.