Knowledge of the dynamic of clinical infections with Asian strains of LSD virus (LSDV) in Bos indicus is scarce. This study reports on the clinical, serological and molecular features of natural infections with LSDV in B. indicus during the first outbreak in Yogyakarta, Indonesia, 2023. Eleven Peranakan ongole (PO) breed cattle with multiple skin lumps were included in the study. Data was collected on lump progression, rectal temperature, anorexia, lameness and oedema, along with serum samples, on five sampling points at four days intervals. Seroconversion was detected using an ELISA, viral DNA in sera was detected using PCR and a phylogenetic tree of the viral DNA sequences was constructed. A Kendall’s tau-b bivariate correlation was conducted to test correlations between variables observed. Results showed that, after lumps, lameness was the most frequently observed clinical feature (9/11), followed by oedema, anorexia (both 6/11) and fever (5/11). Lump presence was strongly correlated with lameness and moderately correlated viral DNA load in sera (r = 0.61, P < 0.01, and r = 0.51, P < 0.01), anorexia was moderately correlated with the course of oedema (r = 0.45, P < 0.01). Younger animals were ill for longer than older individuals. Antibody levels increased on Day eight but declined rapidly yet, remained above the threshold, on day 16. The detection of viral DNA in sera was of short duration and intermittent in a few animals; the virus was closely related to Clade 2 of LSDV. This study provides preliminary knowledge of features of LSDV infection in Indonesia for further studies on vaccination, clinical treatment and prognosis of the disease.