High Intensity Neutron Generator (HINEG) is a facility aiming for neutronics design validation, materials and components irradiation test, nuclear waste transmutation and nuclear technology applications, etc. A high-pressure windowless gas target system is adopted for HINEG to achieve a higher neutron yield. Therefore, a three-stage differential vacuum system has been developed to couple the pressure transition of 6 orders of magnitude to the 300 kV/50 mA high-intensity beam transport in a series of large-diameter pipes. A suitable pumping system has been developed to increases the target pressure which is used to generate D-T neutron yield of 2.1 × 1013 n/s. A windowless pressure transition from high gas pressure (1 × 103 Pa) in the gas target chamber to high vacuum (3 × 10−3 Pa) in the accelerator is reached. In this paper, a new differential pumped vacuum system is designed for HIENG. Innovatively, the newly designed differential vacuum system can not only meet the transport requirements of the high-current low-energy deuteron beam, but also couple the pressure transition of 6 orders of magnitude, which can solve the contradiction of the large-diameter pipe required for high-intensity beam transport and the small diameter pipe needed for the high-pressure difference.The experimental validation and design optimization of differential pumped vacuum system is introduced. The experiment results indicate the validity of the theoretical calculation. Compared to molecular pumps, roots pumps might be more suitable for windowless differential vacuum system coupled to large-diameter apertures and pipes. The design could be used for reference in other windowless gas target systems coupled to accelerator with high-current low-energy ion beam.