WVSPLAGRT (H2) and IGFLIIWV (H3) are two transepithelial transported intestinal peptides obtained from the hydrolysis of hempseed protein with pepsin, which exert antioxidant activity in HepG2 cells. Notably, both peptides reduce the HO-induced reactive oxygen species, lipid peroxidation, and nitric oxide (NO) production levels in HepG2 cells via the modulation of the nuclear factor erythroid 2-related factor 2 and the inducible nitric oxide synthase (iNOS) pathways, respectively. Due to the close link between inflammation and oxidative stress and with the objective of fostering the multifunctional behavior of bioactive peptides, in this study, the molecular characterization of the anti-inflammatory and immunomodulatory properties of H2 and H3 was carried out in HepG2 cells. In fact, both peptides were shown to modulate the production of pro (IFN-γ: -33.0 ± 6.7% H2, = 0.011; -13.1 ± 2.0% H3, = <0.0001; TNF: -17.6 ± 1.7% H2, = 0.0004; -20.3 ± 1.7% H3, = <0.0001; and IL-6: -15.1 ± 6.5% H3, = 0.010)- and anti (IL-10: +9.6 ± 3.1% H2, = 0.010; +26.0 ± 2.3% H3, = < 0.0001)-inflammatory cytokines and NO (-9.0 ± 0.7% H2, = <0.0001; -7.2 ± 1.8% H3, = <0.0001) through regulation of the NF-κB and iNOS pathways, respectively, in HepG2 cells stimulated by lipopolysaccharides.