In this paper we investigate a Principal-Agent problem with moral hazard under Knightian uncertainty. We extend the seminal framework of Holmström and Milgrom by combining a Stackelberg equilibrium with a worst-case approach. We investigate a general model in the spirit of [14]. We show that optimal contracts depend on the output and its quadratic variation, as an extension of the works of [31] (by dropping all the restrictive assumptions) and [44] (by considering a general class of admissible contracts). We characterize the best reaction effort of the agent through the solution to a second order BSDE and we show that the value of the problem of the Principal is the viscosity solution of an Hamilton-Jacobi-Bellman-Isaacs equation, without needing a dynamic programming principle, by using stochastic Perron's method.