Rabies is a neglected zoonotic disease that poses public health and economic challenges in developing countries. Rabies is endemic in Ethiopia causing 35 - 58 human deaths annually and resulting in 209 million USD in economic loss due to cattle death. Method: From April to December 2023, an outbreak of rabies occurred in the Somali Regional State of Ethiopia (SRS). We collected rabies data from two districts of the Somali region, Awbare and Yocale districts, which represent agro-pastoral and pastoral areas of the region. We conducted a joint outbreak investigation, reviewing health facility data and collecting community data. To confirm the outbreak, brain samples were collected from animals (1 camel, 1 donkey, 1 cow and 1 dog) and tested at the Jigjiga Veterinary Regional Laboratory (JVRL) and the Ethiopian Public Health Institute (EPHI). In addition to the investigation, joint community awareness was conducted by the Health Bureau and Livestock Bureau regarding the transmission and public health consequences of the disease. To assess the cost-effectiveness of rabies control, dog vaccination costs, human hospitalization costs, and economic losses due to livestock death (ELLD) were calculated and compared. Result: From May to December 2023, 34 people (Awbare 32, Yocale 2 people) were bitten by suspected rabid dogs, striped polecats, and camels. Thirty two victims were hospitalized and recovered, and two who did not seek health care or went to the hospital late died. The human attacking rate, or cumulative incidence, was 25.5 cases per 100,000 people (95% CI: 18.23_35.7/100,000), while the case fatality rate was 5.9% (95% CI: 0.015–0.22). Ninety one percent (91%) of human exposures were caused by dog bites, while cat, camel, and Ictonyx striatus caused 2.94% each. A majority of victims were male (70.59%) and children under 15 years old (57.14%). The most affected body parts were leg (50%), followed by hand or arm (23.53%), trunk (14.71%), and neck or head (11.76%). Twenty-eight animals, including camels, cattle, and donkeys, were killed or died following a reservoir host bite. Most of the animal suspected cases were caused by dogs (64.29%), followed by jackals (25%), striped polecat (3.57%) and unknown (7.14%). Our cost analysis estimated the PEP cost and ELLD at USD 6144 and USD 23601, respectively. In comparison, the cost required to vaccinate the entire dog population was significantly lower, estimated at USD 3’156. This outbreak also identified the first case of a camel bitten by a striped polecat testing positive for rabies in East Africa. Our economic analysis revealed that early response dog vaccination is economically advantageous and has the potential to reduce human and animal rabies exposure cases. Conclusion and Recommendation: Our observation reveals that rabies is endemic in SRS, where it causes significant public health and economic costs. Rabies vaccination is cost-effective, and we recommend dog vaccination campaign and promotion of health education on rabies using a one health approach.