Abstract: Antarctic krill oil has emerged as one of the most exceptional candidates in the contemporary landscape of global health. There is an escalating demand for high-quality, sustainable, and nutritionally rich food sources. This study aims to evaluate the influence of high-vacuum desolventization on the qualitative attributes of Antarctic krill oil. The relationship between processing parameters and product integrity was elucidated to determine the efficacy of high-vacuum desolventization. The bioactive constituents intrinsic to Antarctic krill oil were conserved for its rich reservoir of beneficial nutrients, including omega-3 fatty acids and astaxanthin. An exhaustive analysis was performed on the residual solvent content, astaxanthin levels, colorimetric properties, oxidative stability, and the pivotal health indices of atherogenic (AI) and thrombogenic (TI) potentials. A holistic assessment was delivered to clarify the desolventization process. The results demonstrated that the high-vacuum desolventization at specific temperatures (like 50°C for 50 min, 60°C for 30 min, and 70°C for 15 min) effectively degraded the residual n-hexane to below the 20 mg/kg benchmark, according to the national standard GB/T 2716-2018. The procedure contributed to the safety and quality of the final product. Moreover, these desolventization protocols were to preserve the astaxanthin levels above the threshold of 30 mg/kg, according to the SC/T 3506-2020 standard for the superior quality of krill oil. Particularly, the thermo-labile bioactive compounds (like astaxanthin) were susceptible to thermal degradation. The compound remained to promote the health attributes of the oil. There was stable oil after desolventized Antarctic krill across a spectrum of parameters, such as color, oxidative stability, and health indices, indicating the robustness of the high-vacuum desolventization. The post-desolventization with negligible variations suggested that the process was highly effective in mitigating the solvent residues with intrinsic nutritional and health-promoting qualities. In summary, the high-vacuum desolventization can serve as an innovative way for the desolventization of Antarctic krill oil. Advanced lipid processing can be a new benchmark for quality and safety. The findings can provide insights into the sustainable and healthful processing of marine resources in the oil industry. Novel techniques can be promoted to fully meet the high quality, nutritionally dense, and sourced sustainable products.