Transgenic crops producing Bacillus thuringiensis (Bt) insecticidal proteins are grown widely for pest control, but the evolution of resistance in target pests could reduce their efficacy. Mutations in genes encoding cadherin, ABC transporter or tetraspanin were linked with resistance to Cry1Ac in several lepidopteran insects, including the cotton bollworm (Helicoverpa armigera), a worldwide agricultural pest. However, the detailed molecular mechanisms by which these mutations confer insect resistance to Cry1Ac remain largely unknown. In this study, we analyzed the midgut transcriptomes of a susceptible SCD strain and three SCD-derived Cry1Ac-resistant strains of H. armigera (SCD-r1, with a naturally occurring deletion mutation of cadherin; SCD-KI, with a knock-in T92C point mutation in tetraspanin; and C2/3-KO, with both ABCC2 and ABCC3 knocked out). Evaluation of midgut transcript profiles of the four strains without Cry1Ac exposure identified many constitutively differentially expressed genes (DEGs) in the resistant SCD-r1 (n = 1355), SCD-KI (n = 1254) and C2/3-KO (n = 2055) strains. Analysis of DEGs in the midguts of each strain after Cry1Ac exposure revealed similar patterns of response to Cry1Ac in the SCD and SCD-r1 strains, but unique responses in the SCD-KI and C2/3-KO strains. Expression of midgut epithelium healing and defense-related genes was strongly induced by Cry1Ac intoxication in the SCD and SCD-r1 strains, while immune-related pattern recognition receptor and effector genes were highly expressed in the SCD-KI strain after Cry1Ac exposure. This study advances our knowledge of the transcriptomic basis for insect resistance to Bt toxins and provides a valuable resource for further molecular characterization of insect response to Cry1Ac toxin in H. armigera and other pest species.