Background Hyperpolarized noble gas MRI helps measure lung ventilation, but clinical translation remains limited. Free-breathing proton MRI may help quantify lung function using existing MRI systems without contrast material and may assist in providing information about ventilation not visible to the eye or easily extracted with segmentation methods. Purpose To explore the use of deep convolutional neural networks (DCNNs) to generate synthetic MRI ventilation scans from free-breathing MRI (deep learning [DL] ventilation MRI)-derived specific ventilation maps as a surrogate of noble gas MRI and to validate this approach across a wide range of lung diseases. Materials and Methods In this secondary analysis of prospective trials, 114 paired noble gas MRI and two-dimensional free-breathing MRI scans were obtained in healthy volunteers with no history of chronic or acute respiratory disease and in study participants with a range of different obstructive lung diseases, including asthma, bronchiectasis, chronic obstructive pulmonary disease, and non-small-cell lung cancer between September 2013 and April 2018 (ClinicalTrials.gov identifiers: NCT03169673, NCT02351141, NCT02263794, NCT02282202, NCT02279329, and NCT02002052). A U-Net-based DCNN model was trained to map free-breathing proton MRI to hyperpolarized helium 3 (3He) MRI ventilation and validated using a sixfold validation. During training, the DCNN ventilation maps were compared with noble gas MRI scans using the Pearson correlation coefficient (r) and mean absolute error. DCNN ventilation images were segmented for ventilation and ventilation defects and were compared with noble gas MRI scans using the Dice similarity coefficient (DSC). Relationships were evaluated with the Spearman correlation coefficient (rS). Results One hundred fourteen study participants (mean age, 56 years ± 15 [standard deviation]; 66 women) were evaluated. As compared with 3He MRI, DCNN model ventilation maps had a mean r value of 0.87 ± 0.08. The mean DSC for DL ventilation MRI and 3He MRI ventilation was 0.91 ± 0.07. The ventilation defect percentage for DL ventilation MRI was highly correlated with 3He MRI ventilation defect percentage (rS = 0.83, P < .001, mean bias = -2.0% ± 5). Both DL ventilation MRI (rS = -0.51, P < .001) and 3He MRI (rS = -0.61, P < .001) ventilation defect percentage were correlated with the forced expiratory volume in 1 second. The DCNN model required approximately 2 hours for training and approximately 1 second to generate a ventilation map. Conclusion In participants with diverse pulmonary pathologic findings, deep convolutional neural networks generated ventilation maps from free-breathing proton MRI trained with a hyperpolarized noble-gas MRI ventilation map data set. The maps showed correlation with noble gas MRI ventilation and pulmonary function measurements. © RSNA, 2020 See also the editorial by Vogel-Claussen in this issue.