Background Lead exposure results in a terrible rise in heat shock protein levels. Objective This research was conducted to look at the effects of lead poisoning on heat shock response, oxidative stress, and inflammatory markers in albino rats, as well as the power of selenium and vitamin E to resist lead toxic effects. Methods Eight groups of albino rats are used. Each group contained six rats where the first group represented the negative control, and the other groups were treated with olive oil, vitamin E, selenium, lead, (vitamin E + lead), (selenium + lead), and (vitamin E + selenium + lead). All the treatments lasted for 28 days. Then, the mRNA expression of interested heat shock proteins (HSP90, HSP70, and HSP60) was assessed. For oxidative stress disruption, we investigated nitric oxide (NO) and malondialdehyde (MDA) content, and enzymatic and non-enzymatic antioxidants activity respectively in rat livers. Results our results revealed the synergetic protective effect of the combination of two antioxidants (vitamin E and selenium) against lead poising. This was clear in regulating HSPs expression, inflammatory markers, glucose, lipid profile, liver functions, and antioxidant enzymes more than the treatment with one antioxidant. Conclusion Pb is a toxic material that can induce HSPs and inflammatory markers expression. Selenium and vitamin E can give excellent effects in ameliorating Pb toxicity when used together.