Phytochemical investigation on the 95% EtOH extract of the whole plants of Zephyranthes grandiflora resulted in the isolation of six new 4a-epi-plicamine-type alkaloids, zephygranditines A-F (1–6), including three novel 11,12-seco-plicamine-type alkaloids. The structures of the isolated compounds were established based on 1D and 2D (1H–1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated alkaloids were tested in vitro for cytotoxic potential against seven malignant melanoma cell lines and inhibitory activity for nitric oxide (NO) production and Cox-1/Cox-2. As a result, alkaloids 1–3 exhibited some cytotoxic activity against all the tested tumor cell lines with IC50 values <20 μM and 1 and 2 displayed anti-inflammatory activity in both assay of inhibitory activity for nitric oxide production and Cox-1/Cox-2. © 2018