The ability to assess farm animals’ mood is important to evaluate their welfare, but practical assessment tools are still lacking. Human research has demonstrated a link between psychological states and the transcriptome of blood immune cells. Therefore, this study aimed to investigate whether blood immune cell transcriptome can be used to assess the animals’ mood using environmental enrichment as a method to generate contrasted welfare states. Pregnant sows of mixed parities were housed in two contrasting conditions throughout gestation (0 to 105 days): a conventional system on a slatted floor (C, n = 36) or an enriched system on accumulated straw with additional space per sow (E, n = 35). The behavior of multiparous sows of low (2nd and 3rd gestation; n = 29) and high (4th gestation or higher; n = 31) parity was observed from G99 to G104 and 14 sows per system were selected for biological sampling. Cortisol concentrations in saliva (G35 and G98), and in the hair (G98), were lower in E sows (P < 0.04). E sows spent more time exploring the pen (P < 0.001), less time chewing enrichment material (P < 0.001) or exhibiting stereotypic behaviors (P = 0.04), and had lower frequencies of agonistic behaviors (P = 0.04). High-throughput sequencing of the blood mononuclear cell transcriptome (G98) identified only 24 differentially expressed genes (DEGs) between C and E sows (adjusted p-value < 0.1, FC < 0.8 or > 1.2). However, parity (894 DEGs) and social dominance (437 DEGs) had a greater effect, and most of the DEGs were related to innate and adaptive immunity pathways. Therefore, these results confirm that long-term environmental enrichment decreases cortisol concentration and positively influences sow behavior. The blood transcriptome did not allow discrimination between housing conditions but it was influenced by another important factor for welfare, such as social dominance in the group.