Leukotriene B₄ (LTB₄) mediates different inflammatory events such as neutrophil migration and pain. The present study addressed the mechanisms of LTB₄-mediated joint inflammation-induced hypernociception. It was observed that zymosan-induced articular hypernociception and neutrophil migration were reduced dose-dependently by the pretreatment with MK886 (1–9 mg/kg; LT synthesis inhibitor) as well as in 5-lypoxygenase-deficient mice (5LO^−/−) or by the selective antagonist of the LTB₄ receptor (CP105696; 3 mg/kg). Histological analysis showed reduced zymosan-induced articular inflammatory damage in 5LO^−/− mice. The hypernociceptive role of LTB₄ was confirmed further by the demonstration that joint injection of LTB₄ induces a dose (8.3, 25, and 75 ng)-dependent articular hypernociception. Furthermore, zymosan induced an increase in joint LTB₄ production. Investigating the mechanism underlying LTB₄ mediation of zymosan-induced hypernociception, LTB₄-induced hypernociception was reduced by indomethacin (5 mg/kg), MK886 (3 mg/kg), celecoxib (10 mg/kg), antineutrophil antibody (100 μg, two doses), and fucoidan (20 mg/kg) treatments as well as in 5LO^−/− mice. The production of LTB₄ induced by zymosan in the joint was reduced by the pretreatment with fucoidan or antineutrophil antibody as well as the production of PGE₂ induced by LTB₄. Therefore, besides reinforcing the role of endogenous LTB₄ as an important mediator of inflamed joint hypernociception, these results also suggested that the mechanism of LTB₄-induced articular hypernociception depends on prostanoid and neutrophil recruitment. Furthermore, the results also demonstrated clearly that LTB₄-induced hypernociception depends on the additional release of endogenous LTs. Concluding, targeting LTB₄ synthesis/action might constitute useful therapeutic approaches to inhibit articular inflammatory hypernociception.