Bone cement implantation syndrome is a critical complication of orthopaedic surgery, characterised by hypotension and hypoxemia. This syndrome is hypothesised to result from obstruction caused by fat droplets and the biochemical release of histamine caused by bone cement components. This study aimed to elucidate the histamine release mechanism, focusing on Mas-related G protein-coupled receptor X2 expressed on mast cells, which is hypothesised to be activated by bone cement components. Using a mast cell-deficient mouse femur fracture model, we examined bone cement's effect on serum histamine. Rat basophil-like cells expressing Mas-related G protein-coupled receptor X2 were exposed to monomethyl methacrylate, a bone cement component, to assess degranulation via β-hexosaminidase release. Our findings demonstrated that histamine levels significantly increased in wild-type mice post-cement application, from 27.7 ± 11.1 to 35.3 ± 12.9 ng/mL (p = 0.016). Furthermore, Mas-related G protein-coupled receptor X2 expressing cells showed a marked increase in β-hexosaminidase release upon monomethyl methacrylate stimulation (p = 4.30 × 10⁻⁵). These results support the hypothesis that activating Mas-related G protein-coupled receptor X2 by monomethyl methacrylate contributes to bone cement implantation syndrome via histamine release. Bone cement implantation syndrome can manifest as a condition involving either peripheral vascular embolism, the release of chemical mediators, or a combination of both. Our research elucidates the role of chemical mediators, particularly histamine-induced vasodilation, in the pathophysiology of bone cement implantation syndrome, providing valuable insights that pave the way for targeted interventions to mitigate this severe complication during orthopaedic surgery.