The biogas production through the anaerobic digestion (AD) of giant reed (Arundo donax L.) biomass has received increasing attention. However, due to the presence of lignin, a low CH4 yield can be obtained. Aiming to improve the CH4 yield from giant reed biomass, the effectiveness of a thermo-chemical pre-treatment based on KOH was evaluated in this paper. The usefulness of a washing step before the AD was also assessed. The pre-treatment led to a specific CH4 yield up to 232 mL CH4 g−1 VS which was 21% higher than that from untreated biomass; the maximum daily rate of production was improved by 42%, AD duration was reduced by 10%, and CH4 concentration in the biogas was increased by 23%. On the contrary, the washing step did not improve the AD process. Besides, washing away the liquid fraction led to biomass losses, reducing the overall CH4 production. The use of a KOH-based pre-treatment appears as a good option for enhancing the AD of giant reed, also presenting potential environmental and agronomical benefits, like the avoidance of salty wastewater production and the likely improvement of the digestate quality, due to its enriched K content.