Lumpy skin disease (LSD) vaccination and epidemiological distribution remain unknown in some parts of Ethiopia including the Sidama regional state. With this, an assessment of LSD vaccine-related problems and serological study was performed in selected districts of Sidama regional state representing three agroecological zones from September 2021 to June 2022. A cross-sectional study of qualitative and quantitative studies was used. The result showed a few portion of respondents know about LSD (29.2%), and vaccinate their cattle (23.3%). 20.8% of the respondents stated LSD occurrence in their vaccinated cattle while focus group discussion with the professionals stated the possible reasons related to electric power disruption that impacted LSD vaccine cold-chain. The other study was on sero-epedimiology of LSD which showed an overall animal and herd level sero-prevalence of 40.8% and 81%, respectively. Higher and lower sero-prevalence was observed in lowland (48%) and highland (28%) areas, respectively. Furthermore, risk factor analysis showed the existence of a significant association between management systems, breed, and body condition score (BCS) of cattle. In conclusion, both qualitative and quantitative study results showed the need for intervention in terms of community-based awareness creation about LSD clinical signs, vaccination advantages, and options for electric power supply together with the frequently updated information on LSD prevalence.