<p>The objective of the present study is to optimize the extraction method for maximum retention of nutritional and bioactive compounds from bitter gourd waste (pomace). Earlier used thermal technology like steam blanching results in loss of nutritional quality due to rise in temperature during heating. But novel non-thermal technologies like ultrasonication and cold plasma offer significant advantages over conventional thermal technologies like retaining nutrients, texture and microbial safety. Also, currently, no data is available on the processing of bitter gourd waste through cold plasma and ultrasonication treatments. So, in this study, novel non-thermal technologies such as cold plasma and ultrasonication are compared with conventional thermal technology i.e. steam blanching. The effects of these technologies as pre-treatments were examined on bitter gourd pomace to monitor the changes in the total phenolic content, total flavonoid content, protein content, along with their total antioxidant activity and microbial load. In the present study, cold plasma emerged as the most effective method for enhancing the total phenolic content (18.52&#xa0;mg GAE/g), reducing microbial load (6.29 *10²&#xa0;CFU/ml), and retaining protein content (4.96%). However, ultrasonication method proved to be superior for maximizing total flavonoid content (10.83&#xa0;mg quercetin equivalent/g), while steam blanching offered the highest total antioxidant activity (45.91% inhibition) in the bitter gourd waste. Overall, the results suggested that cold plasma technology was found to be most effective pre-treatment for retaining maximum nutritional and bioactive compounds. Collectively, these findings are valuable for advancing food processing technologies, promoting sustainable practices, and optimizing nutrient retention.</p> Graphical Abstract <p></p>