Eighteen new jatrophane diterpenoids, euphoesulatins A-R (<b>1</b>-<b>18</b>), and three known diterpenoids (<b>19</b>-<b>21</b>) were isolated from <i>Euphorbia esula.</i> Compounds <b>1</b>-<b>7</b>, <b>14</b>, and <b>18</b> represent a rare type of jatrophane-type diterpenoid containing a nicotinoyloxy group. The absolute configuration of <b>1</b> was determined by X-ray crystallography. The compounds were assayed for their antiosteoporotic activity in a bone-marrow-derived macrophage cell line, and compounds <b>1</b>, <b>8</b>, and <b>10</b> significantly inhibited the formation of osteoclasts, with IC<sub>50</sub> values of 1.2, 3.5, and 2.3 μM, respectively. These three compounds also dose-dependently reduced the activity of nuclear factor activated T-cell cytoplasmic 1. This study reveals the antiosteoporotic effects of jatrophane diterpenoids for the first time.