This study focused on determining the effect of the inoculum to substrate ratio (ISR) on biogas production efficiency from the anaerobic co-digestion of two substrates: synthetic food waste and common reeds (Phragmites australis) that were ground and pre-treated using sodium hydroxide at a concentration of 2% to increase access to their cellulose. It also studied the role of different mixing ratios of the two substrates in improving the stability of the digestion process and increasing biogas production. A series of batch tests were carried out under mesophilic conditions using three ratios of ISR: 1:4, 1:2, and 1:1, and five substrate mixing ratios (synthetic food waste: pre-treated P. australis): 25:75, 50:50, 75:25, 100:0, and 0:100. The results showed low biogas production at the ISR 1:4 (21.58±0.00–44.46±0.01 mL/g volatile solid (VS) added), and the reactors suffered from acidification at the different substrates mixing ratios, while the biogas production increased at an ISR of 1:2, where the reactors with the substrate mixing ratio of 25:75 presented the highest biogas production (82.17±0.62 mL/g VS added), and the digestion process was stable. However, the reactors with substrate mixing ratios of 50:50, 75:25, and 100:0 suffered from acidification effects at this ISR. In contrast, at ISR of 1:1, the reactors did not expose to acidification inhibition at all the substrates mixing ratios, and the highest biogas production was found at synthetic food waste: pre-treated P. australis mixing ratios of 75:25 and 100:0 (76.15±1.85 and 82.47±1.85 mL/g VS added, respectively).