In the search for novel compounds with both survivin inhibitory activity and fluorescence properties, 18 novel longifolene-derived tetralin pyrimidine compounds were designed using survivin as the target and synthesized from the sustainable natural resource longifolene. Their structures were confirmed by IR, NMR, ESIMS, and elemental analysis. The in vitro antiproliferative activities of the target compounds were preliminarily evaluated using the standard MTT assay against MGC-803 (human gastric cancer cell), T24 (human bladder cancer cell), HepG2 (human liver cancer cell), and A549 (human lung adenocarcinoma cell). As a result, some of the target compounds showed better antiproliferative activities than the positive control drug 5-FU, in which, compound 5m had an IC 50 of 1.42 μM against MGC-803 and compound 5l had an IC 50 of 1.79 μM against T24, exhibiting excellent activity. Additionally, the target compounds display moderate or even low cytotoxicity toward human normal liver cells L02. Subsequently, a reasonable and effective 3D-QSAR model was established to study the relationship between the structure of the target compounds and antiproliferative activities and was employed to construct two new compounds with potentially better activity. Meanwhile, molecular docking was performed to study the interaction mode between the compound 5m and survivin protein. Furthermore, the target compounds with significant antiproliferative activity showed noticeable fluorescence properties. In the search for novel compounds with both survivin inhibitory activity and fluorescence properties, 18 novel longifolene-derived tetralin pyrimidine compounds were designed using survivin as the target and synthesized from the sustainable natural resource longifolene.