To effectively alleviate the increasingly serious situation of airspace congestion and flight delays in a multi-airport system, we consider a scheduling problem for multi-airport departure flights in this paper. A mathematical model based on two-stage no-wait hybrid flow-shop is presented for sequencing departure flights in different airports within one terminal area. Moreover, some practical issues which affect the performance of the schedule are also carried out by the Constrained Position Shifting (CPS). Then a CPLEX program is developed and implemented to obtain reasonable solutions within acceptable computation time. Finally, we apply the proposed model and algorithm to a real case study of Shanghai Terminal Area with departure flights from Shanghai HongQiao International Airport and Shanghai PuDong International Airport. The computational results do prove the advantage of the proposed model and the algorithm. An efficient scheduling for departure flights can fully improve the utilization of critical resources and reduce the impact of traffic interaction between airports.