Cryptolepis sanguinolenta and its bioactive alkaloid, cryptolepine have shown anti-inflammatory activity. However, the underlying mechanism of anti-inflammatory action in neuronal cells has not been investigated. In the present study we evaluated an extract of C. sanguinolenta (CSE) and cryptolepine (CAS) on neuroinflammation induced with IL-1β in SK-N-SH neuroblastoma cells. We then attempted to elucidate the mechanisms underlying the anti-neuroinflammatory effects of CAS in SK-N-SH cells. Cells were stimulated with 10 U/ml of IL-1β in the presence or absence of different concentrations of CSE (25-200 μg/ml) and CAS (2.5-20 μM). After 24 h incubation, culture media were collected to measure the production of PGE2 and the pro-inflammatory cytokines (TNFα and IL-6). Protein and gene expressions of cyclooxygenase (COX-2) and microsomal prostaglandin synthase-1 (mPGES-1) were studied by immunoblotting and qPCR, respectively. CSE produced significant (p < 0.05) inhibition of TNFα, IL-6 and PGE2 production in SK-N-SH cells. Studies on CAS showed significant and dose-dependent inhibition of TNFα, IL-6 and PGE2 production in IL-1β-stimulated cells without affecting viability. Pre-treatment with CAS (10 and 20 μM) was also found to inhibit IL-1β-induced protein and gene expressions of COX-2 and mPGES-1. Further studies to determine the mechanism of action of CAS showed inhibition of NF-κBp65 nuclear translocation, but not IκB phosphorylation. At 10 and 20 μM, CAS inhibited IL-1β-induced phosphorylation of p38 MAPK. Studies on the downstream substrate of p38, MAPK-activated protein kinase 2 (MAPKAPK2) showed that CAS produced significant (p < 0.05) and dose dependent inhibition of MAPKAPK2 phosphorylation in IL-1β-stimulated SK-N-SH cells. This study clearly shows that cryptolepine (CAS) inhibits neuroinflammation through mechanisms involving inhibition of COX-2 and mPGES-1. It is suggested that these actions are probably mediated through NF-κB and p38 signalling.