Valorizing agri-food industrial waste is essential for a circular economy, yielding high-value products, waste reduction, technological solutions, employment opportunities, and enhanced food security. This work shows the valorization of seeds generated as residues from the agri-food industries of guava pera (Psidium guajava) and Tommy Atkins mango (Mangifera indica L.), through extraction with supercritical carbon dioxide (scCO2). After the optimization of the initial solid condition of the raw material (i.e., particle size and moisture content), scCO2 pressure and temperature were established through the response surface methodology (RSM) to obtain an oily extract with the highest content in bioactive compounds of commercial relevance, as well as with a high antioxidant capacity. The total amount of oily extract in guava and mango seeds was 14% and 9%, respectively, while the maximum recovery of supercritical extract was 95% from guava seeds at 38 MPa and 50 °C, and 88% from mango seeds at 37 MPa and 63 °C. Bioactive fractions rich in squalene, γ-tocopherol, α-tocopherol, campesterol, β-sitosterol, and stigmasterol were obtained. The best supercritical extraction conditions, in terms of the bioactive fractions richest in minor compounds, were at 17 MPa and 50 °C for guava seeds and at 23 MPa and 63 °C for mango seeds. At these conditions, the highest antioxidant capacities were also found for the extracts. Thus, these bioactive fractions could be used in a variety of products in the cosmetic, food, pharmaceutical, and medical activities due to the beneficial properties of the identified compounds in health as antioxidants, anti-inflammatories, and cholesterol reducers.