Background: Noninvasive identification of amyloid-β (Aβ) is important for better clinical management of mild cognitive impairment (MCI) patients. Objective: To investigate whether radiomics features in the hippocampus in MCI improve the prediction of cerebrospinal fluid (CSF) Aβ42 status when integrated with clinical profiles. Methods: A total of 407 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative were allocated to training (n = 324) and test (n = 83) sets. Radiomics features (n = 214) from the bilateral hippocampus were extracted from magnetic resonance imaging (MRI). A cut-off of <192 pg/mL was applied to define CSF Aβ42 status. After feature selection, random forest with subsampling methods were utilized to develop three models with which to predict CSF Aβ42: 1) a radiomics model; 2) a clinical model based on clinical profiles; and 3) a combined model based on radiomics and clinical profiles. The prediction performances thereof were validated in the test set. A prediction model using hippocampus volume was also developed and validated. Results: The best-performing radiomics model showed an area under the curve (AUC) of 0.674 in the test set. The best-performing clinical model showed an AUC of 0.758 in the test set. The best-performing combined model showed an AUC of 0.823 in the test set. The hippocampal volume model showed a lower performance, with an AUC of 0.543 in the test set. Conclusion: Radiomics models from MRI can help predict CSF Aβ42 status in MCI patients and potentially triage the patients for invasive and costly Aβ tests.