Background Lumpy skin disease is a contagious viral disease of cattle caused by LSDV that results in huge economic losses in the cattle industry. This study characterizes LSDV in cattle through clinicopathological and molecular techniques in selected districts of Wolaita Zone, Southern Ethiopia. Methods A crossectional study was conducted from November 2020 to June 2021 using Real-time polymerase chain reaction and Histopathological techniques to confirm LSDV. Result This study revealed that the percentage of positivity of cattle for LSDV was 36.2%. Clinically, cattle infected with LSDV revealed fever (39–41 °C), nodular lesions on the skin and mucous membranes, and lymphadenopathy. Histopathologically, affected tissue revealed ballooning degenerations of the epidermis, infiltration of mononuclear inflammatory cells, vasculitis, and intracytoplasmic eosinophilic inclusion bodies. RT-PCR confirmed that DNA extracts from skin biopsies of virus isolates were positive for LSDV. Conclusion The present study confirms that LSDV is widely circulating in cattle of selected districts of the Wolaita zone. Thus, effective control measures through regular vaccination and further confirmation of circulating strains of LSDV through detailed molecular analysis should be recommended.