This work aimed to synthesize a series of carboxychalcones and determine their efficacy as neuroprotective agents in vitro. All carboxychalcones were synthesized from terephthalaldehydic acid, an aromatic aldehyde with a carboxy group, using the Claisen-Schmidt condensation method and evaluated through in silico analyses and various biological tests. The potential of chalcones derivatives bearing carboxy groups in the ring as neuroprotective agents was tested by assessing their biological effects in the in vitro model of neural cells (HT-22) inter alia, using the resazurin reduction assay, the LDH release test and flow cytometry-based methods, followed by determining the specific protein expression by Western Blot. Our research suggests that compounds 3b and 3c may possess antioxidant properties. In terms of the potential reactivity of the studied compounds, we discussed HOMO-LUMO descriptors using the DFT formalism and analyzed the vertical excited states (theoretical UV-vis spectra) for two compounds. The computational study proved that the relatively lowest absolute values of the HOMO-LUMO gap, electronegativity, and chemical hardness corresponded to the two derivatives tested in biological assays.