<p>Seven previously unreported sesquiterpenes including three rare 5/5/6-fused tricyclic gymnomitrane-type sesquiterpenes (<b>1</b>–<b>3</b>), an <i>ent</i>-longipinane-type sesquiterpene (<b>4</b>), a cuparane-type sesquiterpene (<b>5</b>), and two chamigrane-type sesquiterpenes (<b>6</b> and <b>7</b>), along with a known chamigrane-type sesquiterpene xylariterpenoid C (<b>8</b>) were isolated from the hydrothermal vent sediment derived fungus <i>Penicillium</i> sp. JWM79-5–1. Their structures were identified on the basis of 1D and 2D NMR, in conjunction with Mosher’s method, X-ray crystallography, and electronic circular dichroism (ECD). The antithrombotic activity of compounds <b>1</b>–<b>6</b> and <b>8</b> was evaluated in arachidonic acid (AA)-induced zebrafish thrombosis model in vivo<i>.</i> The results revealed compound <b>1</b> with potent antithrombotic activity in a concentration-dependent manner. Further, the pro-angiogenic activities of compounds <b>1</b>–<b>6</b> and <b>8</b> were evaluated in a transgenic zebrafish model that expresses <i>vegfr2</i>, the receptor for the angiogenic factor VEGF, tagged with the green fluorescence protein (<i>vegfr2</i>-GFP) through detecting the length of both intersegmental vessels (ISVs) and subintestinal veins (SIVs). The results revealed that compound <b>1</b> exhibited a potent antithrombotic activity while<b> 3</b> revealed a potent pro-angiogenic activity. These findings strongly support drug development of these compounds in cardiovascular disease treatment.</p>