Among the causal risk factors directly promoting the development of coronary and peripheral atherosclerosis are reactive oxygen species and elevated low-density lipoprotein plasma levels. We hereby designed new potent squalene synthase (SQS) inhibitors that may simultaneously tackle the oxidative stress induced by lipid peroxidation. Using previously developed morpholine derivatives as a starting point, we conducted extensive structural changes by either substituting or modifying the morpholine ring, aiming at an optimal SQS-antioxidant pharmacological profile. Compounds 2, 3, and 7 emerged as the most potent bifunctional analogues, displaying IC50 values for SQS inhibition of 0.014, 0.16, and 0.51 μΜ, respectively, and further significantly decreasing lipid peroxidation of hepatic microsomal membranes. The aforementioned activities were also confirmed in vivo since the most promising derivative 2 exhibited a remarkable antihyperlipidemic and antioxidant effect. In conclusion, rational drug design accompanied by structure-activity relationship studies led to compounds combining improved antioxidant and antihyperlipidemic activity that may serve as multifunctional agents against atherosclerosis.