In Drosophila melanogaster, several signaling pathways, including the JAK/STAT pathway, are known to mediate blood cell activation and/or to be involved in the defense against parasitoid wasp infection. How these signals control the cellular defense is not understood for any of them. Here we show that parasitoid wasp infection activates JAK/STAT signaling in the Drosophila larva, not only in blood cells (hemocytes), but also in somatic muscles. In the muscles, JAK/STAT signaling is activated by the cytokines Upd2 and Upd3, which are secreted from circulating hemocytes. Deletion of the upd2 or upd3 genes, but not the related os (upd1) gene, reduces the cellular immune response. In addition, suppression of the JAK/STAT pathway in muscle cells reduces the encapsulation of wasp eggs and the number of circulating effector cells, called lamellocytes. These results suggest that Upd2 and Upd3 are important cytokines, coordinating the cellular immune response of Drosophila. Furthermore, via a JAK/STAT-dependent mechanism, muscles participate in controlling the defense against wasp infection.