Anaerobic co-digestion of peanut hulls and swine manure was investigated. The interaction effects of the total solid percentage (TS%), carbon nitrogen ratio (C/N ratio), and inoculum volume percentage (I%) on the total biogas production and methane content were evaluated using quadratic regression models and response surface methodology (RSM). The results show, with the assistance of the developed quadratic model, that the influence of the three factors on the biogas production and methane content followed the order TS% > I% > C/N ratio. With the assistance of RSM, when the TS%, C/N ratio, and I% were 5.83%, 29.31:1, and 30.00%, respectively, the maximum biogas production (1280.65 mL/g VS) was achieved; when the TS%, C/N ratio, and I% were 5.85%, 34.06:1, and 30.00%, respectively, the highest methane content was obtained (686.06 mL CH4/g VS). The C/N ratio insignificantly affects the biogas production and methane content in this experiment. In the low concentration of anaerobic digestion (AD), the inoculum concentration is positively correlated with the biogas production and methane content. However, in the high-concentration AD, the inoculum concentration is negatively correlated with the biogas production and methane content. To ensure the efficiency of the biogas production and increase the volume utilization of the anaerobic digester, in the case of low I% in anaerobic co-digestion of peanut hulls and swine manure, batch feeding can be adopted by gradually increasing the TS%.