Background: Meyna spinosa (M.S) (Roxb.) ex Link and Oroxylum indicum (O.I) (Linn.) Vent, widely used traditional Northeast Indian medicinal plant used for various purposes, have not yet explored for safety profile. Objective: To investigate the safety profile of M.S (Roxb.) ex Link leaves and O.I (Linn.) Vent stem bark extracts collected from Northeast region of India. Materials and Methods: In this study, mutagenic, cytotoxic, and genotoxic and/or nontoxic potential of these two plant extracts using various toxicological investigations, as per the regulatory test guidelines, were evaluated. The mutagenic, cytotoxic, and genotoxic potential of these two plants were assayed using Ames test, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, comet assay, and micronucleus test in the bone marrow cells. Results: The results demonstrated that the tested doses of M.S (Roxb.) ex Link leaves extract showed mutagenic, cytotoxic, and genotoxic effects, whereas O.I (Linn.) Vent stem bark extracts showed nonmutagenic, noncytotoxic, and nongenotoxic effects. Conclusion: The stem bark extracts of O.I (Linn.) Vent has no mutagenic, cytotoxic, and genotoxic or clastogenic effects in our experimental conditions. However, M.S (Roxb.) ex Link leaves extract caused a significant increase in DNA damage as compared with the positive control, i.e., cyclophosphamide. Thus, the present study revealed that M.S (Roxb.) ex Link leaves extract is toxic, while O.I (Linn.) Vent stem bark extract was found to be safe.