Diopside is one of the most important end-members of clinopyroxene, which is an abundant mineral in upper-mantle petrologic models. The amount of clinopyroxene in upper-mantle pyrolite can be ∼15 vol%, while pyroxenite can contain as high as ∼60 vol% clinopyroxene. Knowing the elastic properties of the upper-mantle diopside at high pressure-temperature conditions is essential for constraining the chemical composition and interpreting seismic observations of region. Here we have measured the single-crystal elasticity of Fe-enriched diopside (Di80Hd20, Di-diopside, and Hd-hedenbergite; also called Fe-enriched clinopyroxene) at high-pressure conditions up to 18.5 GPa by using in situ Brillouin light-scattering spectroscopy (BLS) and synchrotron X-ray diffraction in a diamond-anvil cell. Our experimental results were used in evaluating the effects of pressure and Fe substitution on the full single-crystal elastic moduli across the Di-Hd solid-solution series to better understand the seismic velocity profiles of the upper mantle. Using the third- or fourth-order Eulerian finite-strain equations of state to model the elasticity data, the derived aggregate adiabatic bulk and shear moduli (KS0, G0) at ambient conditions were determined to be 117(2) and 70(1) GPa, respectively. The first- and second-pressure derivatives of bulk and shear moduli at 300 K were (∂KS/∂P)T = 5.0(2), (∂2KS/∂P2)T = –0.12(4) GPa−1 and (∂G/∂P)T = 1.72(9), (∂2G/∂P2)T = –0.05(2) GPa−1, respectively. A comparison of our results with previous studies on end-member diopside and hedenbergite in the literatures shows systematic linear correlations between the Fe composition and single-crystal elastic moduli. An addition of 20 mol% Fe in diopside increases KS0 by ∼1.7% (∼2 GPa) and reduces G0 by ∼4.1% (∼3 GPa), but has a negligible effect on the pressure derivatives of the bulk and shear moduli within experimental uncertainties. In addition, our modeling results show that substitution of 20 mol% Fe in diopside can reduce VP and VS by ∼1.8% and ∼3.5%, respectively, along both an expected normal mantle geotherm and a representative cold subducted slab geotherm. Furthermore, the modeling results show that the VP and VS profiles of Fe-enriched pyroxenite along the cold subducted slab geotherm are ∼3.2% and ∼2.5% lower than AK135 model at 400 km depth, respectively. Finally, we propose that the presence of Fe-enriched pyroxenite (including Fe-enriched clinopyroxene, Fe-enriched orthopyroxene, and Fe-enriched olivine), can be an effective mechanism to cause low-velocity anomalies in the upper mantle regions atop the 410 km discontinuity at cold subudcted slab conditions.