Dopamine (DA) is an essential catecholamine neurotransmitter in the human body responsible for cognitive function. Its irregularities are linked to several neurological illnesses, including Alzheimer’s disease and depression. Therefore, accurate detection of DA is a topic of considerable interest. In the present work, a non-enzymatic electrochemical sensor was fabricated by modifying a carbon paste electrode (CPE) with solution combustion-synthesized high-entropy (Ce1/6Gd1/6Pr1/6Sm1/6Y1/6Zr1/6)O2 oxide nanoparticles. The prepared nanoparticles exhibit a single-phase cubic fluorite structure (Fm-3m) with spongy nanostructures along with a uniform distribution of all principal elements. The prepared high-entropy (Ce1/6Gd1/6Pr1/6Sm1/6Y1/6Zr1/6)O2 oxide nanoparticle-modified CPE electrode material was utilized in the electrochemical detection of DA. The results show that high-entropy oxide nanoparticles improve the electrochemical properties of the modified electrode. The fabricated sensor shows good electrochemical sensing activity with a limit of detection (LOD) of 3.83 μM. The oxygen vacancies played a significant role in improving the DA sensing while enhancing the reproducibility, repeatability, and interference ability.