Abstract Crustacean allergy is a significant health problem worldwide, and tropomyosin (TM) is the major allergen found in crustaceans. Therefore, this study aimed to determine whether high pressure and thermal treatments could reduce the allergic properties of TM. Shrimp protein extracts were treated with high pressure and/or thermal treatment, and the allergenicity of TM was analyzed by competitive inhibition enzyme-linked immunosorbent assays using pooled sera from eight patients with shrimp specific IgE. Compared to the boiling treatment, a reduction with 73.59% in immunoglobulin E (IgE) binding was observed when the samples were treated at 55 °C, 500 MPa for 10 min. Furthermore, in a BALB/c mouse model of allergy, significant reductions in specific IgE titers were observed in mice fed with TM treated with high pressure and heat (TMH), accompanied by reduced histamine levels in serum. Similarly, real-time reverse transcription polymerase chain reaction revealed the decrease in mRNAs encoding interferon-γ, interleukin (IL)-4, and IL-10 in jejunum tissues. TMH had almost no allergenicity in the BALB/c mouse model of TM allergy. Industrial relevance High hydrostatic pressure (HHP) processing can inactivate microorganisms and enzymes, leaving sensory and nutritional quality almost unchanged. Furthermore, HHP could alter allergen conformation and hence decrease allergenic activity in rice, fish, milk and celery that were reported. As a health concern, shrimp allergies have been studied in this work. This study was conducted to determine whether high pressure and heat could reduce the allergic properties of shrimp allergen tropomyosin (TM). In addition, the effects on the allergenicity of TM treated with high pressure and heat (TMH) were characterized using a BALB/c mouse model of allergy. The results showed that TMH has great potential for industrialization to eliminate or decrease allergenicity of food protein.