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Bisindole alkaloids are a source of inspiration for the design and discovery of new-generation anticancer agents. In this study, we investigated the cytotoxic and antiproliferative activities of three spirobisindole alkaloids from the traditional anticancer Philippine medicinal plant <i>Voacanga globosa</i>, along with their mechanisms of action. Thus, the alkaloids globospiramine (<b>1</b>), deoxyvobtusine (<b>2</b>), and vobtusine lactone (<b>3</b>) showed in vitro cytotoxicity and antiproliferative activities against the tested cell lines (L929, KB3.1, A431, MCF-7, A549, PC-3, and SKOV-3) using MTT and CellTiter-Blue assays. Globospiramine (<b>1</b>) was also screened against a panel of breast cancer cell lines using the sulforhodamine B (SRB) assay and showed moderate cytotoxicity. It also promoted the activation of apoptotic effector caspases 3 and 7 using Caspase–Glo 3/7 and CellEvent-3/7 apoptosis assays. Increased expressions of cleaved caspase 3 and PARP in A549 cells treated with <b>1</b> were also observed. Apoptotic activity was also confirmed when globospiramine (<b>1</b>) failed to promote the rapid loss of membrane integrity according to the HeLa cell membrane permeability assay. Network pharmacology analysis, molecular docking, and molecular dynamics simulations identified MAPK14 (p38α), a pharmacological target leading to cancer cell apoptosis, as a putative target. Low toxicity risks and favorable drug-likeness were also predicted for <b>1</b>. Overall, our study demonstrated the anticancer potentials and apoptotic mechanisms of globospiramine (<b>1</b>), validating the traditional medicinal use of <i>Voacanga globosa</i>.