In addition to seven known alkaloids (<b>2</b>, <b>6</b>-<b>11</b>) and 1,2,4-trimethoxybenzene (<b>1</b>), three isoquinoline-derived alkaloids (<b>3</b>-<b>5</b>), namely, duguetinine (<b>3</b>), a compound based on an unprecedented oxahomoaporphine scaffold, and two new 8-oxohomoaporphine alkaloids, duguesuramine (<b>4</b>) and 11-methoxyduguesuramine (<b>5</b>), and a new asarone-derived phenylpropanoid (<b>10</b>) were isolated from the bark of <i>Duguetia surinamensis</i>. The isolation workflow was guided by HPLC-HRESIMS/MS and molecular networking-based analyses. Twenty-four known alkaloids were dereplicated from the <i>D. surinamensis</i> alkaloid-rich fraction network and were assigned by manual MS/MS interpretation. Their cytotoxic potential was evaluated.