Flexible job shop scheduling problem (FJSP), widely prevalent in many intelligent manufacturing industries, is one of the most classic problems of production scheduling and combinatorial optimization. In actual manufacturing enterprises, the setup of machines and the handling of jobs have an important impact on the scheduling plan. Furthermore, there is a trend for a cluster of machines with similar functionalities to form a work center. Considering the above constraints, a new order-driven multi-equipment work center FJSP model with setup and handling including multiple objectives encompassing the minimization of the makespan, the number of machine shutdowns, and the number of handling batches is established. An improved shuffled frog leading algorithm is designed to solve it through the optimization of the initial solution population, the improvement of evolutionary operations, and the incorporation of Pareto sorting. The algorithm also combines the speed calculation method in the gravity search algorithm to enhance the stability of the solution search. Some standard FJSP data benchmarks have been selected to evaluate the effectiveness of the algorithm, and the experimental results confirm the satisfactory performance of the proposed algorithm. Finally, a problem example is designed to demonstrate the algorithm’s capability to generate an excellent scheduling plan.