The present study investigated the impacts of pasteurization and thermosonication on various aspects of modhusuleng (Polygonum microcephalum) leaf juice, including its physico-chemical, functional, and microbial attributes (total plate count, yeast and mold count). Juices underwent thermosonic treatments at varied durations (30, 45, and 60 min) and temperatures (30, 40, and 50 °C), utilizing two distinct frequencies (33 and 44 kHz). The application of pasteurization (PS) and thermosonication (TS) did not exhibit any noticeable effects on pH, total soluble solids (TSS), or titratable acidity (TA). Post TS, there were enhancements in antioxidant activity, total phenolic content (TPC), total flavonoid content (TFC), cloudiness value, browning index, total carotenoid content, and chlorophyll content. However, the ascorbic acid content in the leaf juices decreased post TS. Process optimization was carried out through the application of response surface methodology (RSM). For 33 kHz, the predicted values were - Antioxidant - 68.23 %, TPC - 183.11 mg GAE/100 mL, TFC - 3.15 mg QE/mL, and Ascorbic acid - 24.45, while for 44 kHz, the values were obtained as - Antioxidant - 60.80 %, TPC - 212.97 mg GAE/100 mL, TFC - 3.40 mg QE/mL, and Ascorbic acid - 25.53. The model's suitability is highlighted by the small difference between the expected and actual values. The results revealed that leaf juice samples treated at 50 °C with a frequency of 44 kHz for 60 min exhibited higher TPC, TFC, and antioxidant activity when compared to samples subjected to alternative temperature and frequency conditions. TS also led to a significant reduction in bacterial populations in the juices. While thermal treatment rendered the microbes inert, it adversely impacted the quality indices. The study suggests that modhusuleng juice quality features can be preserved even after undergoing thermosonic processing. TS is suggested as a favorable technique for modhusuleng leaf juice processing, given its potential to enhance antioxidant activity, preserve quality features, and reduce bacterial populations.