For pretreating waste-activated sludge, the combined alkali and microwave pretreatment is a promising hybrid method. To make this pretreatment more economical, moderate conditions were applied for central composite design of the experiments. A quadratic model was established to describe the influence of NaOH dosage and microwave processing time on methane production. The optimal condition was 0.12 g NaOH/g TS treatment for 24 h and 240 W microwave treatment for 10 min. Either single or hybrid pretreatment can significantly accelerate the hydrolysis, but the degree of degradation increases positively as correlated with treatment intensity. Comparing to untreated sludge, the methane yields of microwave-, alkali-, and combined-treated increased to 1.9, 3.4, and 4.6 times, respectively. The SCOD removal rates of the three kinds of treated sludge were 20.6%, 23.0%, and 36.5%, respectively. The single microwave pretreatment efficiently broke the sludge flocs and promoted the release of biodegradable organics as well as nutrients, but there was no advantage in methane production. The existence of NaOH not only eliminated the inhibition caused by microwave, but also improved the degree of degradation.