Diabetes mellitus (DM) is associated with systemic inflammation and neuroinflammation, but the role of β-arrestin 2 in these processes remains poorly understood. The experimental study aimed to assess the effect of β-arrestin 2 deficiency on the pro-inflammatory state of mice with streptozotocin-induced diabetes. Male C57BL/6J mice and mice with the global β-arrestin 2 gene knockout (Arrb2-/-) were divided into four groups: non-diabetic wild type mice (WT, n = 8), diabetic wild-type mice (WTd, n = 8), non-diabetic knockout mice (KO, n = 8) and diabetic knockout mice (KOd, n = 9). Arrb2 knockout delayed the development of hyperglycemia: on day 39, blood glucose levels were significantly higher in WTd mice than in KOd mice (22.3 ± 8.09 vs. 14.37 ± 7.65 mmol/L, p < 0.05). Arrb2-/- mice also showed increased systemic inflammatory markers: the baseline percentage of neutrophils in KO mice was 2.6-fold higher than in WT mice (p < 0.0001). Starting from day 18 KOd mice had significantly higher neutrophil counts compared to KO and WTd (p < 0.05). β-Arrestin 2 deficiency was associated with increased mRNA expression of the genes encoding pro-inflammatory cytokines and protease-activated receptors. The most pronounced changes included a significant increased Il6 mRNA expression in the hippocampus of KO compared to WT (2.9-fold, p < 0.01), increased Tnf expression in the cerebral cortex (4.3-fold for KO/WT and 2.0-fold for KOd/WTd) and the hippocampus (3.2- and 2.3-fold, respectively) of Arrb2-/- animals compared to appropriate wild type groups (p < 0.05), as well as the increased Par1 and Par4 expression in the cerebral cortex and hippocampus of Arrb2-/- mice (2.4–7.3-fold, p < 0.01). These findings suggest that β-arrestin 2 deficiency is associated with a pro-inflammatory phenotype in the CNS and may contribute to inflammation dysregulation in DM.