Anaerobic codigestion of food waste (FW) and sewage sludge for hydrogen production is a realistic approach to concurrently degrade the organic wastes and produce renewable energy. The study evaluated the individual and interactive effects of FW carbon/nitrogen ratio (C/N), FW proportion in a cosubstrate, the initial pH, and the moisture content on hydrogen production by a central composite design and the response surface methodology (RSM) in order to optimize the parameters for biohydrogen production. The result revealed that all the four factors investigated had significant impacts on specific hydrogen production based on the dry weight (SHPDW), of which the moisture content was found to be the most significant one (P < 0.0001). In addition to moisture content, it should be emphasized that FW C/N deserved taking into consideration during the anaerobic codigestion. As for the interactive effect, moisture content-initial pH and moisture content-FW proportion had a significant influence on SHPDW (P < 0.05). The optimal operational conditions obtained by RSM were FW C/N 18.55, FW proportion in the cosubstrate 0.60, initial pH 5.88, and moisture content 94% with a SHPDW of 144.96 mL of H-2/g dry-weight. Model validation proved the effectiveness of the prediction model in evaluating the various parameter combinations for achieving maximum hydrogen production. Besides, the optimization of wet weight-based specific hydrogen production (SHPWW) as adopted in this study considered the economic effect of the whole process, which is quite practical when considering the scaling-up of the hydrogen production process.