This research study evaluates various pre-treatments to improve sewage sludge solubilization prior to treatment by mesophilic anaerobic digestion. Microwave, thermal, and sonication pre-treatments were compared as these pre-treatments are the most commonly used for this purpose. The solubilization of sewage sludge was evaluated through the variation in soluble total organic carbon (sTOC, mg/L) and soluble total nitrogen (sTN, mg/L). Thermal and microwave pre-treatments increased sTOC/VS by 19.2% and 83.4% (VS, total volatile solids), respectively, after applying lower specific energy through (20 kJ/g TS, approximately) (TS, total solids) unlike the sonication pre-treatment, which required 136 kJ/g TS. Although sTN content did not increase significantly with the pre-treatments with respect to sTOC, both showed proportional trends. Sonication pre-treatments allowed the highest increase in volatile fatty acids (VFA) with respect to the raw sewage sludge (15% increment VFA/sTOC). Methane production with and without pre-treatment was also evaluated. Methane production increased by 95% after applying sonication pre-treatment compared to the methane production of raw sewage sludge. Thermal and microwave pre-treatments entailed lower improvements (29% and 20%, respectively). Economically, thermal pre-treatments were the most viable alternative at real scale.