Tomato plant waste (TPW) is a significant agricultural byproduct that has been often underutilized. Recent studies have shown that its use to obtain methane in an anaerobic digestion (AD) process is viable. However, there is not much information available on studies to improve methane production from this substrate using statistical methods for optimization processes such as central composite design (CCD). For this investigation, CCD was adopted to analyze the effect of S/I ratio (substrate/inoculum ratio) (0.32–1.12), temperature (27–43 °C), and inoculum concentration (10.35–20.95 g VS/L) on methane generation and volatile solids (VS) removal in a batch AD system mono-digestion of TPW. The highest average value of methane yield was found to be 210.8 mL CH4/g VS (S/I ratio 0.48, 40 °C, and 18.80 g VS/L), and the highest average value of VS removal was found to be 36.9% (S/I ratio 1.12, 35 °C, and 15.65 g VS/L). We obtain a model with a better fit for the VS removal (R2 = 0.9587) than for the methane production (R2 = 0.9156). Temperature and S/I ratio were the factors most important for methane production and VS removal, respectively.