Large‐scale strongly nonlinear and nonconvex mixed‐integer nonlinear programming (MINLP) models frequently appear in optimization‐based process synthesis, integration, intensification, and process control. However, they are usually difficult to solve by existing algorithms within acceptable time. In this study, we propose two robust homotopy continuation enhanced branch and bound (HCBB) algorithms (denoted as HCBB‐FP and HCBB‐RB) where the homotopy continuation method is employed to gradually approach the optimum of the NLP subproblem at a node from the solution at its parent node. A variable step length is adapted to effectively balance feasibility and computational efficiency. The computational results from solving four existing process synthesis problems demonstrate that the proposed HCBB algorithms can find the same optimal solution from different initial points, while the existing MINLP algorithms fail or find much worse solutions. In addition, HCBB‐RB is superior to HCBB‐FP due to much lower computational effort required for the same locally optimal solution.