The Assen Fe ore deposit is a banded iron formation (BIF)-hosted orebody, occurring in the Penge Formation of the Transvaal Supergroup, located 50 km northwest of Pretoria in South Africa. Most BIF-hosted Fe ore deposits have experienced post-depositional alteration including supergene enrichment of Fe and low-grade regional metamorphism. Unlike most of the known BIF-hosted Fe ore deposits, high-grade hematite (> 60% Fe) in the Assen Fe ore deposit is located along the lithological contacts with dolerite intrusions. Due to the variability in alteration levels, identifying the lithologies present within the various parts of the Assen Fe ore deposit, specifically within the weathering zone, is often challenging. To address this challenge, machine learning was applied to enable the automatic classification of rock types identified within the Assen Fe ore mine and to predict the in-situ Fe grade. This classification is based on geochemical analyses, as well as petrography and geological mapping. A total of 21 diamond core drill cores were sampled at 1 m intervals, covering all the lithofacies present at Assen mine. These were analyzed for major elements and oxides by means of X-ray fluorescence spectrometry. Numerous machine learning algorithms were trained, tested and cross-validated for automated lithofacies classification and prediction of in-situ Fe grade, namely (a) k-nearest neighbors, (b) elastic-net, (c) support vector machines (SVMs), (d) adaptive boosting, (e) random forest, (f) logistic regression, (g) Naive Bayes, (h) artificial neural network (ANN) and (i) Gaussian process algorithms. Random forest, SVM and ANN classifiers yield high classification accuracy scores during model training, testing and cross-validation. For in-situ Fe grade prediction, the same algorithms also consistently yielded the best results. The predictability of in-situ Fe grade on a per-lithology basis, combined with the fact that CaO and SiO2 were the strongest predictors of Fe concentration, support the hypothesis that the process that led to Fe enrichment in the Assen Fe ore deposit is dominated by supergene processes. Moreover, we show that predictive modeling can be used to demonstrate that in this case, the main differentiator between the predictability of Fe concentration between different lithofacies lies in the strength of multivariate elemental associations between Fe and other oxides. Localized high-grade Fe ore along with lithological contacts with dolerite intrusion is indicative of intra-basinal fluid circulation from an already Fe-enriched hematite. These findings have a wider implication on lithofacies classification in weathered rocks and mobility of economic valuable elements such as Fe.