Inhibiting the polarization or survival of tumor-associated macrophages through blocking CSF-1/CSF-1R signal transduction has become a promising strategy for cancer immunotherapy. Herein, a series of (<i>Z</i>)-1-(3-((1<i>H</i>-pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)-3-(isoxazol-3-yl)urea derivatives were designed, synthesized, and evaluated as novel and orally highly effective CSF-1R inhibitors for colorectal cancer immunotherapy. Among these derivatives, compound <b>21</b> was found to possess excellent CSF-1R inhibitory activity (IC<sub>50</sub> = 2.1 nM) and potent antiproliferative activity against colorectal cancer cells. Compound <b>21</b> inhibited the progression of colorectal cancer by suppressing the migration of macrophages, reprograming M2-like macrophages to the M1 phenotype, and enhancing the antitumor immunity. More importantly, compound <b>21</b>, as a single agent, showed significantly superior <i>in vivo</i> anticolorectal cancer efficacy over PLX3397, highlighting a promising candidate for the immunotherapy of colorectal cancer.