Despite the substantial impact of rivers on the global marine litter problem, riverine litter has been accorded inadequate consideration. Therefore, our objective was to detect riverine litter by utilizing middle-scale multispectral satellite images and machine learning (ML), with the Tisza River (Hungary) as a study area. The Very High Resolution (VHR) images obtained from the Google Earth database were employed to recognize some riverine litter spots (a blend of anthropogenic and natural substances). These litter spots served as the basis for training and validating five supervised machine-learning algorithms based on Sentinel-2 images [Artificial Neural Network (ANN), Support Vector Classifier (SVC), Random Forest (RF), Naïve Bays (NB) and Decision Tree (DT)]. To evaluate the generalization capability of the developed models, they were tested on larger unseen data under varying hydrological conditions and with different litter sizes. Besides the best-performing model was used to investigate the spatio-temporal variations of riverine litter in the Middel Tisza. According to the results, almost all the developed models showed favorable metrics based on the validation dataset (e.g., F1-score; SVC: 0.94, ANN: 0.93, RF: 0.91, DT: 0.90, and NB: 0.83); however, during the testing process, they showed medium (e.g., F1-score; RF:0.69, SVC: 0.62; ANN: 0.62) to poor performance (e.g., F1-score; NB: 0.48; DT: 0.45). The capability of all models to detect litter was bounded to the pixel size of the Sentinel-2 images. Based on the spatio-temporal investigation, hydraulic structures (e.g., Kisköre Dam) are the greatest litter accumulation spots. Although the highest transport rate of litter occurs during floods, the largest litter spot area upstream of the Kisköre Dam was observed at low stages in summer. This study represents a preliminary step in the automatic detection of riverine litter; therefore, additional research incorporating a larger dataset with more representative small litter spots, as well as finer spatial resolution images is necessary.