Silkworms, a model lepidopteran insect, have a very simple diet. Artificial diets as an alternative nutrient source for silkworms are gradually being developed. To understand the effects of various nutrients on the growth and development of silkworms, we studied the transcriptomic differences in the midgut and head tissues of male and female silkworms fed either fresh mulberry leaves or artificial diets. In the artificial diet group, compared with the control group (fed mulberry leaves), 923 and 619 differentially expressed genes (DEGs) were identified from the midgut, and 2969 and 3427 DEGs were identified from the head, in female and male silkworms. According to our analysis, the DEGs were mainly involved in the digestion and absorption of nutrients and silkworm innate immunity. These experimental results provide insights into the effects of different foods, such as artificial diets or fresh mulberry leaves, on silkworms.