We consider the Brans-Dicke (BD) theory of gravity and explore the cosmological implications of the sign-changeable interacting holographic dark energy (HDE) model in the background of Friedmann-Robertson-Walker (FRW) universe. As the system's infrared (IR) cutoff, we choose the future event horizon, the Granda-Oliveros (GO) and the Ricci cutoffs... For each cutoff, we obtain the density parameter, the equation of state (EoS) and the deceleration parameter of the system. In case of future event horizon, we find out that the EoS parameter, $w_{D}$, can cross the phantom line, as a result the transition from deceleration to acceleration expansion of the universe can be achieved provided the model parameters are chosen suitably. Then, we investigate the instability of the sign-changeable interacting HDE model against perturbations in BD theory. For this purpose, we study the squared sound speed $v_s^2$ whose sign determines the stability of the model. When $v_s^2<0$ the model is unstable against perturbation. For future event horizon cutoff, our universe can be stable (${v}^{2}_s>0$) depending on the model parameters. Then, we focus on GO and Ricci cutoffs and find out that although other features of these two cutoffs seem to be consistent with observations, they cannot leads to stable dominated universe, except in special case with GO cutoff. Our studies confirm that for the sign-changeable HDE model in the setup of BD cosmology, the event horizon is the most suitable horizon which can passes all conditions and leads to a stable DE dominated universe. (read more)