Sargassum muticum is an important source of bioactive polysaccharides; hence, high hydrostatic pressure (HHP) was used to improve their extraction efficiency. Response surface methodology and a Box-Behnken full factorial design were employed to assess and optimize the effects of extraction conditions on the yield, total sugars, total sulfated sugars and antioxidant activity of S. muticum extracts. The extraction yield ranged between 32 and 40.4% independently of the extraction conditions or seaweed solid/liquid ratio resulting in average increases of 3.6 to 4.8-fold for total sugars and sulfated sugars, as compared to conventional extraction. Extracts displayed improved antioxidant activities, yet maximum values were achieved under different optimum conditions of HHP processing, for example, 5–5.5 min, 300 MPa and 1 g of dry seaweed for yield. In conclusion, the optimal HHP technology conditions described in this paper enables to obtain enriched bioactive polysaccharide S. muticum extracts. Practical Applications: High hydrostatic pressure (HHP) is a suitable method used to improve the extraction of natural ingredients with added value both in terms of nutritional value as in biological properties from different natural sources. In this study it was intended to evaluate the potential and the effectiveness of HHP to obtain extracts concentrated in bioactive polysaccharides from the brown seaweed Sargassum muticum. A new and possible strategy to valorize this invasive brown seaweed rich in sulfated polysaccharides with several health benefits associated. The main results have demonstrated that HHP increased extractability (higher extraction yields) and bioactivity from the seaweed S. muticum, providing extracts with higher content in polysaccharides which can be used as ingredients to develop novel functional foods.