IL-37 is an anti-inflammatory member of the IL-1 family that dampens inflammation associated with many noncommunicable diseases. However, mechanisms of IL-37 regulation remain understudied. We aimed to investigate the enzymatic cleavage of IL-37 that potentiates extracellular signalling, as well as pathways of IL-37 secretion. In human monocytes, mature IL-37 (mIL-37) was released following canonical NLRP3 inflammasome activation. The release of IL-37 was blocked by inhibiting plasma membrane permeability and in gasdermin-D-deficient THP-1 cells. While the cleavage of IL-37 was found to be constitutive, the release of mIL-37 was blocked in NLRP3-deficient THP-1 cells and by NLRP3 inhibitor MCC950 in THP-1s and primary human monocytes. IL-37 secretion also occurred after 18-h exposure to LPS, independently of the alternative NLRP3 inflammasome. This LPS-dependent IL-37 secretion required plasma membrane permeability, but not conventional protein secretion apparatus. Mutagenesis of the suggested caspase-1 cleavage site (D20) or the proposed alternative cleavage site (V46) did not completely block IL-37 processing. Therefore, we propose a novel pathway in which IL-37 is cleaved by caspase-1-independent mechanisms and released following canonical and alternative NLRP3 inflammasome triggers by differential pathways.