Quercetin (QU) is a flavonoid found in different fruits and vegetables. Studies report that QU may have positive effects on neurological diseases. However, the effect of QU on 4-aminopyridine (4-AP)-induced neurodegeneration in neuronal cells is still not fully elucidated. In this study, the effects of QU on 4-AP-induced hippocampal neuron damage in vitro and the possible role of oxidative stress and endoplasmic reticulum stress in this effect were investigated. The study was carried out using the HT-22 hippocampal neuronal cell line. The effect of pre-treatment with QU on cell viability after 4-AP-induced neuronal damage was determined by the XTT test. Cells were evaluated histopathologically for apoptotic nuclear change (ANC) using DAPI staining. The effects of QU on oxidative stress (total oxidant state (TOS) and total antioxidant status (TAS)) occurring after neuronal damage were evaluated with colorimetric commercial kits and endoplasmic reticulum stress markers (activating transcription factor 4 (ATF-4) and C/EBP homologous protein). (CHOP) was measured with the ELISA kits. While the cell viability rate decreased in the cells treated with 4-AP, it was determined that pre-treatment with QU reversed this situation. In terms of histopathology, treatment with 4-AP increased the number of ANC, while QU pre-treatment reduced it. In addition, in terms of biochemical evaluations, TOS, ATF-4, and CHOP increased in neuronal cells after 4-AP, and QU was determined to suppress this increase. In addition, QU normalized the decreased TAS levels following the 4-AP application. As a result, in the HT-22 cell line, it was found that QU treatment had a neuroprotective effect by suppressing oxidative stress and endoplasmic reticulum stress in 4-AP-induced neuronal damage.