Our lab has been developing a deuterium-deuterium (DD) neutron generator-based neutron activation analysis (NAA) system to quantify metals and elements in the human body in vivo. The system has been used to quantify metals such as manganese, aluminum, sodium in bones of a living human. The technology provides a useful way to assess metal exposure and to estimate elemental deposition, storage and biokinetics. It has great potential to be applied in the occupational and environmental health fields to study the association of metal exposure and various health outcomes, as well as in the nutrition field to study the intake of essential elements and human health. However, the relatively low sensitivity of the system has greatly limited its applications. Neutron moderation plays an important role in designing an IVNAA facility, as it affects thermal neutron flux in irradiation cave and radiation exposure to the human subject. This study aims to develop a novel thermal neutron enhancement method to improve the sensitivity of the in vivo neutron activation analysis (IVNAA) system for elemental measurement but still maintain radiation dose. Utilizing a compact DD neutron source, we propose a new and practical moderator design that combines high density polyethylene with heavy water to enhance thermal neutrons by reducing thermal neutron absorption. All material dimensions are calculated by PHITS, a general-purpose Monte Carlo simulation program. The improvement of the new design predicted by the Monte Carlo simulation for the quantification of one of the elements, manganese was verified by experimental irradiation of manganese-doped bone equivalent phantoms. For the same radiation dose, a 67.9% thermal neutron flux enhancement is reached. With only 4.2% increase of radiation dose, the simulated thermal neutron flux and activation can be further increased by 84.2%. A 100% thermal neutron enhancement ratio is also achievable with a 20% dose increase. The experimental results clearly show higher manganese activation gamma ray counts for each specific phantom, with a significantly reduced minimum detection limit. Additionally, the photon dose was suppressed. The thermal neutron enhancement method can increase the number of useful neutrons significantly but maintain the radiation dose. This greatly decreased the detection limit of the system for elemental quantification at an acceptable dose, which will broadly expand the application of the technology in research and clinical use. The method can also be applied to other neutron medical applications, including neutron imaging and radiotherapy.