Flavonoids (quercetin, luteolin) and carotenoids (lycopene, lutein) were combined at different molecular ratios in a total concentration of 8 μM to investigate their antioxidant interactions. Cellular uptake of carotenoids, the expression of carotenoid transporters, the ROS scavenging ability, and antioxidant enzymes activities were compared in HUVEC, Caco-2, and L-02 cells. Combinations with flavonoids in the majority showed stronger antioxidant activity. Lycopene combined with quercetin at ratio 1:5 showed stronger ROS scavenging activities, increased 18, 12, and 12 Cellular antioxidant activity (CAA) units in HUVEC, Caco-2, and L-02 cells, respectively, and promoted SOD and CAT activities than individual component. The cell uptake of carotenoids was enhanced by flavonoids in antioxidant synergistic groups, while dampened by flavonoids in antagonistic groups in HUVEC cells. The synergistic group (lycopene:quercetin = 1:5) increased lycopene uptake by 271%, while antagonistic group (lutein:quercetin = 5:1) decreased lutein uptake by 17%. Flavonoids modulated the effects of carotenoids on the expression of active transporters scavenger receptor class B type I (SR-BI) or Niemann-Pick C1-like 1 (NPC1L1). The synergistic group (lycopene:quercetin = 1:5) increased the expression of SR-BI compared to individual lycopene treatment in HUVEC and Caco-2 cells. Thus, a diet rich in both flavonoids and lycopene possesses a great antioxidant activity, especially if a higher amount of flavonoids is included.