Background: Due to their therapeutic properties and easy access, in Mexican culture, plants are used to treat several diseases. This is the case of Datura inoxia and Turnera diffusa, which affect their central nervous system with psychotropic, anticholinergic, analgesic, and stimulating properties. Objectives: In this research, extracts D1 (methanolic), D2 (chloroformic), and D3 (hexanoic) from D. inoxia and T1 (ethanolic), T2 (chloroformic), and T3 (hexanoic) from T. diffusa were evaluated to determine their neurotoxic and neuroprotective activity in vitro. Materials and Methods: Neurotoxic activity was evaluated in PC-12 cells exposed to the extracts at concentrations ranging from 3.12 to 200 μg/mL. The neuroprotective activity was evaluated by pretreating PC-12 cells with the extracts and subsequently exposing them to neurotoxic compound glutamate. In both assays, cell viability was evaluated with 4-(3-[4-iodophenyl]-2-[4-nitrophenyl]-2H-5-tetrazolio)-1,3-benzene disulfonate (WST-1). Antioxidant activity was studied with the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, and antiapoptotic activity was evaluated with the caspase-3 fluorescent assay. Results: T. diffusa was more neurotoxic than D. inoxia, and both plants showed neuroprotective activity at low concentrations. T. diffusa had more antioxidant activity than D. inoxia. Neither plant had antiapoptotic activity. Conclusion: Extract D1 of D. inoxia and T1 of T. diffusa showed neuroprotective activity, and both extracts had the lowest neurotoxic effect in vitro.