To strike a better balance between gas quality and production cost of biomass-based syngas, a process for high-safety and cost-effective syngas production is designed and studied, which takes advantage of biomass O2-enriched air gasification with 40−70% O2 purity and methanation synthesis. Based on the simulation data, the process is evaluated from techno-economic aspects, including syngas composition, higher heat value (HHV), upper and lower explosive limits (UEL and LEL), toxicity, unit production cost (UPC) and levelized cost of energy (LCOE). Five kinds of biomass are studied as feedstock. The effects of O2 purity, methanation pressure, feedstock cost, and plant scale are determined, respectively. The results show that O2 purity is an important parameter for technical performance, while methanation pressure is a minor parameter except for exergy efficiency. With respect to cost indicators, feedstock cost, and plant scale are crucial variables; by contrast, O2 purity plays a relatively minor role. This process can generate non-toxic syngas containing 33.2−34.9 vol.% CH4. The UEL and LEL are about 34% and 12%, and the average explosive range is about 22%. The HHVs of syngas generated from five kinds of feedstock sit between 13.67−14.33 MJ/m3, and the exergy efficiency achieves 68.68%. The UPC varies between 0.05 $/Nm3 and 0.27 $/Nm3, and the LCOE varies between 3.78 $/GJ and 18.28 $/GJ. When the plant scale is rational, the process shows strong competitiveness in either UPC or LCOE. The techno-economic results demonstrate that the studied process offers an alternative and sustainable pathway to supply gaseous fuel for low-income areas.