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Marine sponges have been recognized as a rich source of potential anti-proliferative metabolites. Currently, there are two sponge-derived anti-cancer agents (a macrolide and a nucleoside) isolated from the Porifera phylum, suggesting the great potential of this sponge as a rich source for anti-neoplastic agents. To search for more bioactive metabolites from this phylum, we examined the EtOAc extract of <i>Theonella</i> sp. sponge. We isolated seven compounds (<b>1</b>–<b>7</b>), including four 4-methylene sterols (<b>1</b>–<b>4</b>), two nucleosides (<b>5</b> and <b>6</b>), and one macrolide (<b>7</b>). Among them, theonellasterol L (<b>1</b>) was identified for the first time, while 5′-<i>O</i>-acetyl-2′-deoxyuridine (<b>5</b>) and 5′-<i>O</i>-acetylthymidine (<b>6</b>) were the first identified deoxyuridine and thymidine derivatives from the sponge <i>Theonella</i> sp. These structures were elucidated based on their spectroscopic data. The anti-proliferation activity of compounds <b>1</b>–<b>7</b> against the MCF-7, MDA-MB-231, T-47D, HCT-116, DLD-1, K562, and Molt 4 cancer cell lines was determined. The results indicated that the 14-/15-oxygenated moiety played an important role in the antiproliferative activity and the macrolide derivatives dominated the anti-proliferative effect of the sponge <i>Theonella</i> sp. The in silico analysis, using a chemical global positioning system for natural products (ChemGPS-NP), indicated an anti-proliferative mode of actions (MOA) suggesting the potential applications of the isolated active metabolites as anti-proliferative agents.