In the present study, cold atmospheric plasma (CAP) was employed as a pretreatment method for the extraction of phenolic compounds from spent coffee grounds (SCGs). The impact of CAP treatment conditions, i.e., thickness of the SCGs layer (mm), distance between the plasma source and the SCGs layer (mm) and duration of CAP treatment (min), on the total phenol content, in vitro antioxidant activity, as well as caffeine and chlorogenic acid content of SCGs, was investigated. The process parameters were optimized with the aid of response surface methodology (RSM). After optimizing the CAP pretreatment conditions, the CAP-treated SCGs were subjected to ultrasound-assisted extraction using ethanol as the extraction solvent. The optimum conditions for CAP treatment identified, i.e., thickness, 1 mm; distance, 16 mm; and duration, 15 min, led to a significant enhancement in the recovery of bioactive compounds from SCGs compared to those obtained from untreated SCGs. Total phenolic content and antioxidant activity significantly increased (i.e., TPC from 19.0 ± 0.7 to 24.9 ± 1.4 mg GAE/100 g dry SCGs, ADPPH from 106.7 ± 5.01 to 112.3 ± 4.3 μmol Trolox/100 g dry SCGs, AABTS from 106.7 ± 5.01 to 197.6 ± 5.8 μmol Trolox/100 g dry SCGs, ACUPRAC from 17938 ± 157 to 18299 ± 615 μmol Trolox/100 g dry SCGs). A significant increase in caffeine content from 799.1 ± 65.1 mg to 1064 ± 25 mg/100 g dry SCGs and chlorogenic acid content from 79.7 ± 15.3 mg to 111.3 ± 3.3 mg/100 g dry SCGs, was also observed. Overall, CAP pre-treatment can be used to enhance the recovery of bioactive compounds from SCGs.