Purpose Considerable progress has been made in the assessment and management of non-small cell lung cancer (NSCLC) patients based on mutation status in the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene (KRAS). At the same time, NSCLC management through KRAS and EGFR mutation profiling faces challenges. In the present work, we aimed to evaluate a comprehensive radiomics framework that enabled prediction of EGFR and KRAS mutation status in NSCLC patients based on radiomic features from low-dose computed tomography (CT), contrast-enhanced diagnostic quality CT (CTD), and positron emission tomography (PET) imaging modalities and use of machine learning algorithms. Methods Our study involved NSCLC patients including 150 PET, low-dose CT, and CTD images. Radiomic features from original and preprocessed (including 64 bin discretizing, Laplacian-of-Gaussian (LOG), and Wavelet) images were extracted. Conventional clinically used standard uptake value (SUV) parameters and metabolic tumor volume (MTV) were also obtained from PET images. Highly correlated features were pre-eliminated, and false discovery rate (FDR) correction was performed with the resulting q-values reported for univariate analysis. Six feature selection methods and 12 classifiers were then used for multivariate prediction of gene mutation status (provided by polymerase chain reaction (PCR)) in patients. We performed 10-fold cross-validation for model tuning to improve robustness, and our developed models were assessed on an independent validation set with 68 patients (common in all three imaging modalities). The average area under the receiver operator characteristic curve (AUC) was utilized for performance evaluation. Results The best predictive power for conventional PET parameters was achieved by SUV peak (AUC 0.69, p value = 0.0002) and MTV (AUC 0.55, p value = 0.0011) for EGFR and KRAS, respectively. Univariate analysis of extracted radiomics features improved AUC performance to 0.75 (q-value 0.003, Short-Run Emphasis feature of GLRLM from LOG preprocessed image of PET with sigma value 1.5) and 0.71 (q-value 0.00005, Large Dependence Low Gray-Level Emphasis feature of GLDM in LOG preprocessed image of CTD with sigma value 5) for EGFR and KRAS, respectively. Furthermore, multivariate machine learning-based AUC performances were significantly improved to 0.82 for EGFR (LOG preprocessed image of PET with sigma 3 with variance threshold (VT) feature selector and stochastic gradient descent (SGD) classifier (q-value = 4.86E-05) and 0.83 for KRAS (LOG preprocessed image of CT with sigma 3.5 with select model (SM) feature selector and SGD classifier (q-value = 2.81E−09). Conclusion Our work demonstrated that non-invasive and reliable radiomics analysis can be successfully used to predict EGFR and KRAS mutation status in NSCLC patients. We demonstrated that radiomic features extracted from different image-feature sets could be used for EGFR and KRAS mutation status prediction in NSCLC patients and showed improved predictive power relative to conventional image-derived metrics.