Lumpy Skin Disease (LSD) is a transboundary viral infection of cattle and buffaloes that has expanded rapidly across Asia, Africa. This study examined ecological, climatic and molecular determinants of LSDV outbreaks using field data, laboratory diagnostics and spatial modeling. Climatic analysis showed that warm, humid conditions significantly increased outbreak intensity, with incidence rising by 16% per 1°C increase in temperature. Rainfall and humidity peaks during monsoon seasons were strongly correlated with vector abundance, leading to predictable seasonal outbreaks in India and Ethiopia. Land use changes, including pasture expansion and deforestation, intensified livestock wildlife interactions, while shared water sources emerged as critical transmission hubs (p = 0.006). High cattle density (>10 heads/km²) sustained viral circulation beyond peak climatic windows. Wildlife reservoirs contributed to cryptic transmission, with buffaloes showing antibody prevalence of 7-28% and PCR positivity in skin scabs (14.3%) and blood (11.1%). Molecular assays confirmed cattle skin biopsies as reliable diagnostic samples (56.6%), while detection in ticks (32.0%) and biting flies (30.0%) reinforced the role of vectors. Spatial cluster analysis identified high risk districts, and predictive models (SARIMA) captured seasonal peaks. An integrated risk zonation framework combining ecological and molecular indicators stratified regions into low, moderate and high risk, supporting targeted vaccination, vector control, and surveillance under a One Health approach.