To better understand the role of dopamine D<sub>4</sub> receptor (D<sub>4</sub>R) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for D<sub>4</sub>R were discovered starting from the brain penetrant and D<sub>4</sub>R selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1<i>H</i>)-one (<b>6</b>). In particular, the D<sub>4</sub>R antagonist <b>24</b>, showing the highest affinity and selectivity over D<sub>2</sub>R and D<sub>3</sub>R within the series (D<sub>2</sub>/D<sub>4</sub> = 8318, D<sub>3</sub>/D<sub>4</sub> = 3715), and the biased ligand <b>29</b>, partially activating D<sub>4</sub>R G<sub>i</sub>-/G<sub>o</sub>-protein and blocking β-arrestin recruitment, emerged as the most interesting compounds. These compounds, evaluated for their GBM antitumor activity, induced a decreased viability of GBM cell lines and primary GBM stem cells (GSC#83), with the maximal efficacy being reached at a concentration of 10 μM. Interestingly, the treatment with both compounds <b>24</b> and <b>29</b> induced an increased effect in reducing the cell viability with respect to temozolomide, which is the first-choice chemotherapeutic drug in GBM.