Spent coffee grounds (SCGs) are currently considered abandoned landfill waste, despite retaining valuable organic compounds, especially with a high protein content of 15.21±0.25 and oil content of 12.07±0.09 g/g dried SCG. As a result, SCGs could serve as a potential source of valuable ingredients. However, utilizing a single technical strategy of green extraction was insufficient for extracting the target compounds and hydrolyzing proteins. This work aimed to optimize the operating parameters of enzyme-assisted (EAE), microwave-assisted (MAE), and subcritical water (SWE) extractions using a response surface methodology. The parameters investigated were papain to substrate ratio of 0.1–0.5 and duration of 15–180 minutes for EAE, power of 100–600 watts and duration of 2–10 minutes for MAE, and temperature of 110–160°C and duration of 5–30 minutes for SWE. The effects of the combined techniques on three responses, including the degree of hydrolysis (%DH), water-soluble protein content (WSPC), and antioxidant properties, were investigated. The results showed that EAE, at a papain to substrate ratio of 0.5 and a duration of 15 minutes, generated the %DH of 100% and provided the WSPC in the range of 400 to 800 mg/mL. Besides, MAE provided the highest %DH of 12% at 600 watts and 10 min, while SWE produced the maximum %DH of 14% at 160°C at 20 min. Hence, the WSPC of MAE and SWE extracts were comparable at ~250 mg/mL. Furthermore, ultrafiltration fractionated the targeted protein hydrolysate to a molecular weight of less than 10 kDa and partially removed intense color pigments. This work demonstrated that the valorization of SCGs not only reduces the amount of waste but also yields functional cosmeceutical and nutraceutical ingredients with commercial benefits.