Peel (MPLE), pulp extract (MPPE) and essential oil (MPO) of Citrus × tangelo were studied for their chemical composition and for their ability to act on the expression of the low-density lipoprotein (LDL) receptor and proprotein convertase subtilisin/kexin 9 (PCSK9), two key players in cholesterol metabolism, in the human hepatocarcinoma cell line Huh7. MPPE demonstrated the ability to induce the LDL receptor and to reduce PCSK9. Chemical characterization of the extracts was conducted via LC-DAD-MS for MPLE and MPPE and via GC-MS for MPO. The main compounds isolated from MPLE and MPPE were ferulic acid, narirutin, 3'-methoxy-narirutin, nobiletin, 3-methoxynobiletin and tangeretin. MPPE significantly induced the LDL receptor (+1.43 ± 0.49-fold vs. basal) and suppressed PCSK9 levels (-64% ± 24% vs. basal). Among the different isolated compounds, ferulic acid showed the most interesting modulation of both the LDL receptor (+1.26 ± 0.14-fold vs. basal) and PCSK9 (-59% ± 14% vs. basal), showing potential cholesterol-lowering properties.