Background <p>Chemotherapy is an effective approach for cancer treatment, but drug resistance and toxicity have become a major hurdle. Photodynamic therapy (PDT) has emerged as a promising strategy with relatively minimal side effects, while phytocompounds of medicinal plants are increasingly recognized as effective therapeutic agents.</p> Purpose <p>This study aimed to assess the potential of <i>Fagoina indica</i> (FI) extract in combination with low-dose Paclitaxel (PTX) and benzoporphyrin derivative (BPD)-mediated photodynamic therapy (BPD-PDT) to determine whether such a multimodal approach can enhance therapeutic efficacy against cancer cells.</p> Methods <p>The cytotoxic effects of FI, PTX, and BPD, individually and in combinations (FI + PTX, FI + BPD-PDT, and FI + PTX+BPD-PDT), were assessed against Hep-2 cells using the MTT assay. Morphological changes in treated cells were observed under an inverted microscope. PDT was performed with a 670&#xa0;nm laser at fluencies of 2.5&#xa0;J/cm² and 5&#xa0;J/cm² (power density, 0.28&#xa0;W/cm²), and intracellular ROS was observed under an inverted fluorescence microscope. The Chou-Talalay method was used to determine the combination index (CI) and evaluate the synergistic effect of the drugs.</p> Results <p>The dose-dependent cytotoxic effect was observed in cells treated with the FI extract. Furthermore, FI extract, as an anti-cancer agent, enhanced the therapeutic effect in PTX-based chemotherapy, BPD-PDT, and chemo-PDT (tri-combination), demonstrating synergistic effects (CI &lt; 1).</p> Conclusion <p>The findings suggest that FI extract enhanced the therapeutic efficacy of PTX and BPD-PDT even at low doses. PDT-induced ROS production played a crucial role in enhancing treatment efficacy, particularly in tri-combination, while minimizing drug doses. More research is needed to isolate the significant bioactive compounds in the FI extract responsible for its anticancer activity.</p> Graphical Abstract <p></p>