This paper proposes an extension of the mixed no-wait flowshop scheduling problem (MNFSP) which considers sequence-dependent setup times (SDSTs). A mixed integer linear programming model is presented to solve small problems with respect to the makespan criterion. Due to the strong NP-hardness of the research problem, an effective and efficient metaheuristic, called pairwise iterated greedy (PIG) algorithm, is proposed to solve medium- and large-size problems. Extensive computational results reveal that the proposed PIG algorithm significantly outperforms the compared algorithm under the same limited computational time. Since MNFSP with SDSTs is widely used in modern manufacturing systems, this innovative research will help to narrow the gap between scheduling theory and practical applications.