The increasing population creates excess pressure on the plantation and production of fruits and vegetables across the world. Consumption demand during the whole year has made production compulsory in the covered production system (greenhouse). Production, harvesting, processing, transporting, and distribution chains of fruit and vegetables have resulted in a huge amount of wastes as an alternative source to produce biofuels. In this study, optimization of two pretreatment processes (NaOH and HCl assisted thermal) was investigated to enhance methane production from fruit and vegetable harvesting wastes (FVHW) that originate from greenhouses. NaOH concentration (0–6.5%), HCl concentration (0–5%), reaction temperature (60–100 °C), solid content (1–5%), time of reaction (1–5 h), and mixing speed (0–500 rpm) were chosen in a wide range of levels to optimize the process in a broad design boundary and to evaluate the positive and negative impacts of independent variables along with their ranges. Increasing NaOH and HCl concentrations resulted in higher COD solubilization but decreased the concentration of soluble sugars that can be converted directly into methane. Thus, the increasing concentrations of NaOH and HCl in the pretreatments have resulted in low methane production. The most important independent variables impacting COD and sugar solubilization were found to be chemical concentration (as NaOH and HCl), solid content and reaction temperature for the optimization of pretreatment processes. The high amount of methane productions in the range of 222–365 mL CH4 gVS−1 was obtained by the simple thermal application without using chemical agents as NaOH or HCl. Maximum enhancement of methane production was 47–68% compared to raw FVHW when 5% solid content, 1-hour reaction time and 60–100 °C reaction temperature were applied in pretreatments.