In the current study, we examined the ability of limonoids, including limonin, limonin glucoside (LG) and curcumin, to inhibit proliferation of human colon cancer (SW480) cells. Additionally, we studied the effect of combining these two classes of natural compounds on inhibition of proliferation and the possible mode of cytotoxicity. The SW480 cells were treated with compounds individually and in combination to understand the effect on cell death, DNA fragmentation, caspase-3 activity and the expression of Bax, Bcl-2 and caspase-3 proteins. Results of cell proliferation assays suggest that combinations of limonoids with curcumin at three different ratios (1 : 3, 1 : 1 and 3 : 1) to a final concentration of 50 ppm demonstrated up to 96% inhibition of cell proliferation. The MTT assay results were also confirmed by counting viable cells. Further, incubation of cells with combinations of limonoids and curcumin resulted in elevation of total cellular caspase-3 activity by 3.5–4.0 fold along with a 2- to 4-fold increase in the Bax/Bcl-2 ratio. The expression of pro-caspase-3 and its cleaved products in cells treated with curcumin (individually or combination) indicates higher potency of the combination to induce apoptosis. For the first time, this study provides compelling evidence of the pharmacodynamic additive effect of limonoids and curcumin in inhibiting human colon cancer cells. The above results were also confirmed by fluorescence microscopy of SW480 cells treated with limonoids, curcumin and combination, after tagging with fluorescent probes. These results suggest that consumption of curcumin and limonoids together may offer greater protection against colon cancer.