Spent coffee grounds (SCG) contain bioactive compounds. In this work, given the increasing demand to valorize waste and use green technologies, SCG were submitted to extraction by carbon dioxide (CO2) in supercritical and liquid conditions. The extraction parameters were varied to obtain the maximum yield with the maximum antioxidant activity. The use of supercritical and liquid CO2with 5% ethanol for 1 h provided yields (15 and 16%, respectively) comparable to those obtained by control methods for 5 h and extracts with high total polyphenolic contents (970 and 857 mg GAE/100 g oil, respectively). It also provided extracts with DPPH (3089 and 3136 μmol TE/100 g oil, respectively) and FRAP (4383 and 4324 μmol TE/100 g oil, respectively) antioxidant activity levels higher than those of hexane extracts (372 and 2758 μmol TE/100 g oil, respectively) and comparable to those of ethanol (3492 and 4408 μmol TE/100 g oil, respectively). The SCG extracts exhibited linoleic, palmitic, oleic, and stearic acids (predominant fatty acids) and furans and phenols (predominant volatile organic compounds). They were also characterized by caffeine and individual phenolic acids (chlorogenic, caffeic, ferulic, and 3,4-dihydroxybenzoic acids) with well-known antioxidant and antimicrobial properties; therefore, they could be used in the cosmetic, pharmaceutical, and food sectors.