<jats:title>Abstract</jats:title><jats:p>Cultivation of the fungal strain <jats:italic>Eurotium rubrum</jats:italic>, an endophytic fungus that was isolated from the inner tissue of stems of the mangrove plant <jats:italic>Hibiscus tiliaceus</jats:italic>, resulted in the isolation of two new dioxopiperazine derivatives, namely, dehydrovariecolorin L (<jats:bold>1</jats:bold>) and dehydroechinulin (<jats:bold>2</jats:bold>), together with eight known dioxopiperazine compounds including variecolorin L (<jats:bold>3</jats:bold>), echinulin (<jats:bold>4</jats:bold>), isoechinulin A (<jats:bold>5</jats:bold>), dihydroxyisoechinulin A (<jats:bold>6</jats:bold>), preechinulin (<jats:bold>7</jats:bold>), neoechinulin A (<jats:bold>8</jats:bold>), neoechinulin E (<jats:bold>9</jats:bold>), and cryptoechinuline D (<jats:bold>10</jats:bold>). The structures of the isolated compounds were determined by extensive analysis of their spectroscopic data as well as by comparison with literature. Compounds <jats:bold>1, 2, 9</jats:bold>, and <jats:bold>10</jats:bold> were investigated for their <jats:italic>α</jats:italic>,<jats:italic>α</jats:italic>‐diphenyl‐<jats:italic>β</jats:italic>‐picrylhydrazyl (DPPH) radical‐scavenging activity. In addition, the new compounds, <jats:bold>1</jats:bold> and <jats:bold>2</jats:bold>, were evaluated for their cytotoxic activity against the P‐388, HL‐60, and A549 cell lines.