Mild-temperature thermo-alkaline pretreatment of spent coffee grounds (SCG) was studied to improve its solubilization and methanation. The simultaneous effects of NaOH concentration (0–0.2 M) and temperature (60–90 °C) were investigated. Significant solubilization of SCG was achieved by the pretreatment, particularly under high-NaOH-concentration and high-temperature conditions. However, adding NaOH above a certain concentration adversely affected the methane production. Therefore, the degree of solubilization (SD) correlated poorly with methane yield (Ym). Response surface models of SD and Ym were successfully generated. The maximum response of SD (36.4%) was obtained at 0.18 M NaOH and 90.0 °C, while that of Ym (263.31 mL CH4/g COD added) was obtained at 0.13 M NaOH and 70.5 °C. Hydrogenotrophic Methanospirillum species were the dominant methanogens in all the SCG digestion tests. It is likely that NaOH concentration had a more significant influence on the development of microbial community structure, particularly of methanogens than temperature.