In a classification context, the Youden index, in addition to being a powerful measure of the performance of diagnostic markers and identifying the optimal cut-off point, has also been shown to be an effective measure to be maximized to combine biomarkers. However, in a high-dimensional background, this method may lead to overfitting, mainly due to the noise caused by considering irrelevant regressors. Hence, to reduce this side effect and increase the robustness and interpretability of the solution, the challenge is not only to combine the features but also to select them, obtaining a sparse result. There are several methods to perform feature selection. One of the most performing solution is to adopt regularization techniques.We propose the Penalized Youden Index Estimator (PYE), a method based on the Youden index and various penalization terms, capable of searching for the best selection and combination of biomarkers at the same time, maximizing this index. Depending on the considered regularization term, L12, L1, Elastic Net, SCAD, and MCP, we propose different versions of PYE. Being the objective function possibly non-convex, we also propose a modified accelerated proximal gradient algorithm to optimize PYE. To test the effectiveness of our approach, a wide simulation study on synthetic and real high-dimensional datasets is presented, comparing the performance of our proposal with some of the most popular existing methods.The results show how PYE, in its different versions, returns alternative solutions with respect to the considered existing methods. In some cases more sparse, in others with a preferable balance among accuracy, selection, and which biomarkers have been considered relevant.