||Heterosis is a common phenomenon in plants and animals and the underlying mechanisms are diverse. Here we used the two widely used silkworm hybrid systems as model and generated multi-omics to address two uncertain issues, i.e., possible intrinsic association of different hybrid strategies and epigenetic mechanism, in contribution of the silkworm heterosis. We demonstrated that there were dramatic differences in silk gland transcriptomic landscapes between the two systems, including differential expressed genes and differential expression pattern in the hybrid vigorous offspring compared to their parents. Hybrid vigor of quaternary hybrid system was mainly due to the up-regulated genes and parental dominant up expression pattern, which were mainly involved in multiple transport processes, cellular nitrogen compound catabolic and the glucose metabolic process as well as tricarboxylic acid cycle (TCA cycle). In contrast, the hybrid vigor of the binary system was caused by the down-regulated genes and transgressive down expression pattern, which were mainly involved basic nitrogen synthesis metabolism and operation of the body. We also demonstrated that DNA methylation could contribute to hybrid vigor via regulating gene expression of some heterosis-related genes. Generally, we illuminated two alternative competent mechanisms that may contribute to formation of silkworm heterosis, both of which took advantage of efficient utilization of energy and nitrogen for silk production.