In this paper, the multiple‐choice knapsack problem with setups is tackled with an iterative method, where both local branching and descent method cooperate. First, an iterative procedure is designed for solving a series of mixed integer programming problems combined with a special reduced subproblem; that is, a combined model built by injecting some valid cardinality constraints. Second, the local branching‐based learning strategy is embedded into an iterative search to mimic the variable neighborhood descent method, such that the local branching strategy drives the search process for enhancing the quality of the solutions. Third, the proposed method is experimentally analyzed on benchmark instances extracted from the literature, where its provided (lower) bounds are compared to those reached by methods published in the literature and the Cplex solver. Finally, its performance is evaluated by providing a statistical analysis.