The Crohn’s disease pathogenesis has been proposed to involve a hypoactive innate immune response and impaired acute inflammatory response. Recently, vitamin D3 has been shown to induce expression of the innate immune receptor, NOD2. Herein, PMA-differentiated THP-1 cells were treated with the active form of vitamin D3, 1,25(OH)2D3, and assessed for release of the pro-inflammatory cytokine IL-1β. We present novel findings that 1,25(OH)2D3 induces the release of IL-1β from PMA-differentiated THP-1 cells. Further, circulating vitamin D3, 25(OH)D3, was also able to induce the IL-1β response. Both 1,25(OH)2D3-induced and 25(OH)D3-induced IL-1β release were found to be dependent on the NLRP3 inflammasome. These novel findings support a beneficial role for vitamin D3 in Crohn’s disease; by boosting basal IL-1β secretion from macrophages, vitamin D3 could help counteract the impaired innate immune and acute inflammatory responses seen in this disease.