This paper numerically investigates the impact of non-uniform boundary heat fluxes on the local and global Nusselt numbers of a circular pipe in fully developed turbulent flow regime. The numerical study is carried out basing on a validated three-dimensional CFD model under a series of prescribed sinusoidal wall heat fluxes. Results show that local Nusselt number fluctuation is remarkable under the heat flux with large non-uniformity and the local fluctuation ratio relatives to the uniform boundary condition is within the range of −26% to +15%. The phase-difference between heat flux profile and Nusselt number profile is expounded via mathematical treatment. To explore the underlying mechanism of the foregoing phenomenon, the analytical tool of field synergy principle is employed and is executed in a more rigorous way. It indicates that the local heat transfer fluctuation attributes to the local synergy-angle change in the very near-wall region. Besides, the average Nusselt number is also investigated. It is shown that, for a fixed amount of total heat flux, the average Nusselt number slightly decreases when the boundary heat flux changes into non-uniform, which dues to the global enlargement of synergy angle as well as the global augmentation of entropy generation increment.