In this paper, we study the existence of positive solutions for a changing-sign perturbation tempered fractional model with weak singularity which arises from the sub-diffusion study of anomalous diffusion in Brownian motion. By two-step substitution, we first transform the higher-order sub-diffusion model to a lower-order mixed integro-differential sub-diffusion model, and then introduce a power factor to the non-negative Green function such that the linear integral operator has a positive infimum. This innovative technique is introduced for the first time in the literature and it is critical for controlling the influence of changing-sign perturbation. Finally, an a priori estimate and Schauder’s fixed point theorem are applied to show that the sub-diffusion model has at least one positive solution whether the perturbation is positive, negative or changing-sign, and also the main nonlinear term is allowed to have singularity for some space variables.