Twelve new resorcylic acid lactones (RALs) including three new 16-membered RALs (<b>1a</b>, <b>1b</b> and <b>2</b>), eight new 14-membered RALs (<b>3</b>-<b>10</b>), and one new 12-membered RAL (<b>11</b>), along with five known 14-membered RALs (<b>12</b>-<b>16</b>), were identified from the fermentation of the soil-derived fungus <i>Ilyonectria</i> sp. sb65. Their structures were established by detailed analyses of 1D and 2D NMR, HRESIMS, and X-ray diffraction crystallography. All new compounds were evaluated for their cytotoxic effects against three human cancer cell lines, along with their potential as TRAIL sensitizers in TRAIL-resistant A549 human lung adenocarcinoma cells and their <i>in vitro</i> immunosuppressive effects against ConA-induced T-cell and LPS-induced B-cell proliferation.