Second-hand smoking poses a serious threat to children`s health, leading to increased risks of illness and death. We targeted to examine how luteolin (Lu) and/or quercetin (Qu) supplements could protect against oxidation and DNA damage are caused by nicotine in young rats. The Lu effect was compared with Qu. Fifty rats were divided to five groups, as follows: (1) control group without treatment; (2) only nicotine (Ni) (0.75 mg/kg); (3) Qu supplement (50 mg/kg/day) with nicotine; (4) luteolin supplement (50 mg/kg/day) with nicotine; and (5) combination  of Qu and Lu (50 mg/kg) for each along with Ni. After 8 weeks, serum, liver, and lung samples were collected. Rats` body weight parameters showed considerable decreases in the Ni group compared to other groups. The liver function enzymes, and malondialdehyde (MDA) value were considerably increased in Ni rats when compared to the control group. The Ni rats showed a notable reduction in endogenous antioxidant enzymes. The Lu and combined groups showed considerable enhancement in all mentioned parameters compared to the Ni group. At the cellular level, the extent of DNA damage was significantly increased in Ni-injected rats, which showed no fragmentation in the Lu+Qu combined administered group. The prophylactic impact of Lu versus nicotine oxidation was similar to Qu. Data indicated that Lu functions by enhancing the antioxidant defense mechanism, modulating lipid peroxidation levels, and ultimately safeguarding DNA in serum and tissues. Combining Lu and Qu led to a synergetic effect, leveraging their respective antioxidant abilities to combat the nicotine oxidative stress.