As well-known antibiotic-producing and filamentous bacteria, streptomycetes can be an ideal model to study the effects of microgravity on microbial development and antibiotic production. In this study, the model organism Streptomyces coelicolor A3(2) was exposed to simulated microgravity (SMG) on a rotating clinostat and microgravity (μg) on the Shenzhou-8 spacecraft. The strain exhibited some similar responses under both conditions. Compared with the controls, its life cycle in agar medium was shortened relatively, and the sporulation process was accelerated with higher accumulation of the gray spore pigment; the liquid cultures yielded more cell biomass, coupled with thicker, more fragmented, and well-dispersed hyphae of the μg spaceflight samples. Global transcriptional analysis verified that most of the differentially expressed genes involved in morphological differentiation of S. coelicolor were upregulated during days 4-6 under SMG conditions, notably the whi genes (whiD, sigF, and whiE). Production of actinorhodin (ACT) in agar cultures decreased under both conditions while undecylprodigiosin (RED) was produced earlier, which were consistent with the transcriptional levels of act and red gene clusters. Meanwhile, expression of the gene clusters for calcium-dependent antibiotic (CDA), methylenomycin (MMY), and a cryptic polyketide (CPK) was unchanged, downregulated, and upregulated, respectively, the latter of which might contribute to the enhanced activity of S. coelicolor against Bacillus subtilis under microgravity. Our study provides new insights into the morphological and secondary metabolic responses of streptomycetes to microgravity.