Purpose: To develop a machine learning-derived radiomics approach to simultaneously discriminate epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene (KRAS), Erb-B2 receptor tyrosine kinase 2 (ERBB2), and tumor protein 53 (TP53) genetic mutations in patients with non-small cell lung cancer (NSCLC). Methods: This study included consecutive patients from April 2018 to June 2020 who had histologically confirmed NSCLC, and underwent pre-surgical contrast-enhanced CT and post-surgical next-generation sequencing (NGS) tests to determine the presence of EGFR, KRAS, ERBB2, and TP53 mutations. A dedicated radiomics analysis package extracted 1672 radiomic features in three dimensions. Discriminative models were established using the least absolute shrinkage and selection operator to determine the presence of EGFR, KRAS, ERBB2, and TP53 mutations, based on radiomic features and relevant clinical factors. Results: In 134 patients (63.6 ± 8.9 years), the 20 most relevant radiomic features (13 for KRAS) to mutations were selected to construct models. The areas under the curve (AUCs) of the combined model (radiomic features and relevant clinical factors) for discriminating EGFR, KRAS, ERBB2, and TP53 mutations were 0.78 (95% CI: 0.70–0.86), 0.81 (0.69–0.93), 0.87 (0.78–0.95), and 0.84 (0.78–0.91), respectively. In particular, the specificity to exclude EGFR mutations was 0.96 (0.87–0.99). The sensitivity to determine KRAS, ERBB2, and TP53 mutations ranged from 0.82 (0.69–90) to 0.92 (0.62–0.99). Conclusions: Machine learning-derived 3D radiomics can simultaneously discriminate the presence of EGFR, KRAS, ERBB2, and TP53 mutations in patients with NSCLC. This noninvasive and low-cost approach may be helpful in screening patients before invasive sampling and NGS testing.