Ticks are hematophagous vectors of great medical and veterinary importance because they transmit numerous pathogenic microorganisms to humans and animals. The argasid Ornithodoros erraticus is the main vector of tick-borne human relapsing fever and African swine fever in the Mediterranean Basin. Tick enterocytes express bioactive molecules that perform key functions in blood digestion, feeding, toxic waste processing and pathogen transmission. To explore new strategies for tick control, in this work we have obtained and compared the midgut transcriptomes of O. erraticus female ticks before and after a blood meal and identified the genes whose expression is differentially regulated after feeding. The transcript sequences were annotated, functionally and structurally characterised and their expression levels compared between both physiological conditions (unfed females and fed females at 2 days post-engorgement). Up to 29,025 transcripts were assembled, and 9290 of them corresponded to differentially expressed genes (DEGs) after feeding. Of these, 4656 genes were upregulated and nearly the same number of genes was downregulated in fed females compared to unfed females. BLASTN and BLASTX analyses of the 29,025 transcripts allowed the annotation of 9072 transcripts/proteins. Among them, the most numerous were those with catalytic and binding activities and those involved in diverse metabolic pathways and cellular processes. The analyses of functional groups of upregulated DEGs potentially related to the digestion of proteins, carbohydrates and lipids, and the genes involved in the defence response and response to oxidative stress, confirm that these processes are narrowly regulated in ticks, highlighting their complexity and importance in tick biology. The expression patterns of six genes throughout the blood digestion period revealed significant differences between these patterns, strongly suggesting that the transcriptome composition is highly dynamic and subjected to important variation along the trophogonic cycle. This may guide future studies aimed at improving the understanding of the molecular physiology of tick digestion and digestion-related processes. The current work provides a more robust and comprehensive understanding of the argasid tick digestive system.