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Allergic diseases, which affect up to 20–30% of the world population, are still therapeutic challenge for allergists. Tetracyclines, which belong to an antibiotic drug family that possesses a striking variety of non-antibiotic properties, have been successfully applied to a wide range of diseases. However, their roles in allergic conjunctivitis and anaphylaxis and their underlying anti-allergy mechanisms remain elusive. Here, we reported that treatment with doxycycline significantly reduced IgE release from mouse B cells and the degranulation and inflammatory cytokines production of mouse mast cells (MCs) activated by IgE-dependent way. Furthermore, doxycycline treatment significantly inhibited histamine-induced vascular hyperpermeability in vitro. Mechanistically, the doxycycline-mediated inhibition of B cells, MCs and histamine may occur via modulation of the PI3K/Akt pathway. In vivo, our results demonstrated that treatment with doxycycline significantly attenuated clinical symptoms of mouse models of experimental allergic conjunctivitis (EAC) with a significant decrease in inflammatory cell frequency, IgE production, histamine release, and a decrease in TNF-α and IL-4 production. Using mouse models of MCs-dependent passive systemic anaphylaxis (PSA), we further confirmed anti-allergy effects of doxycycline and doxycycline-mediated inhibitory effects on MCs. Furthermore, our results showed that doxycycline significantly attenuate histamine-induced systemic anaphylaxis-like reaction (HISA) with a significantly downregulation of PI3K/Akt/eNOS/VE-cadherin pathway. The doxycycline-mediated anti-allergy effects during EAC, PSA and HISA were abrogated when an Akt activator, SC79, was administered. These findings suggest that doxycycline inhibits B cell, MC and histamine function and attenuates experimental allergic conjunctivitis and systemic anaphylaxis by possible modulating the PI3K/Akt pathway.