India is facing a new wave of Lumpy skin disease outbreaks since May 2022, spreading in more than 22 states and causing morbidity to more than 29 lakh animals and mortality to more than 2 lakh animals. Lack of specific antiviral treatment restores symptomatic therapeutic interventions. However, in the advent of large no. of cases and severity of disease, investigations on specific antiviral drugs are imperative. This scientific study was conducted on a group of LSD-affected cattle (n = 40) from the trans-Himalayan region of Kashmir (Jammu and Kashmir). The affected cattle were subjected to different treatments, including acyclovir (n = 27), symptomatic treatment (n = 7), and ivermectin (n = 6), along with supportive drugs. The animals were carefully monitored and compared both within and between groups at various intervals (0-96 hr) using a two-way analysis of variance (ANOVA). Significant (P ≤ 0.05) improvement in regaining rectal temperature, respiration rate, and heart rate was noted 48 hours after treatment in a group of LSD-affected animals (n = 27) treated with acyclovir at a dose rate of 1 mg/kg body weight (small cattle) to 1.5 mg/kg (large cattle) intravenously in 500 ml normal saline along with supportive drugs including enrofloxacin (2.5 mg/kg), combination of meloxicam (0.25 mg/kg) and paracetamol (7.5 mg/kg) and pheniramine maleate (0.5 mg/kg) all intramuscularly, compared to group of LSD affected cattle (n = 6) treated with ivermectin (0.2 mg/kg subcutaneously) and supportive drugs and another group of LSD affected cattle (n = 7) treated symptomatically with only supportive drugs. Acyclovir treated group showed a significant (P ≤ 0.05) decrease in total leucocyte count, lymphocyte, and basophil count from 0 hour to 96 hour of treatment (23.00 ± 0.534 to 5.59 ± 0.208; 13.97 ± 0.310 to 3.43 ± 0.126; 0.11 ± 0.003 to 0.03 ± 0.001 respectively). Significant (P ≤  0.05) decrease in total oxidative status (TOS: 73.31%) and increase in total antioxidant status (TAS: 59.9%) was observed in acyclovir treated group followed by ivermectin treated group (TOS: 68.05% and TAS: 27.16%) compared to symptomatically treated group (TOS: 42.41% and TAS: 18.75%). Acyclovir being comparatively more specific antiviral agent than ivermectin may have helped in amelioration of clinical severity and regaining of normal physiological, hematological, and oxidative indices in LSD-affected animals. The current study demonstrates expedited recovery, diminished clinical severity, and re-establishment of physiological, hematological and oxidative markers in animals subjected to acyclovir treatment, followed by animals administered with ivermectin, when compared to animals receiving symptomatic treatment. However, further studies are required to investigate safety or adverse effects, if any.