The Mai Kenetal-Werii area in northern Ethiopia consists mainly of metavolcanics, metavolcanoclastics, and metasedimentary rocks. This study investigates the provenance and depositional setting of the low-grade metasedimentary rocks of the area using whole-rock geochemistry. The major and trace element compositions were analyzed by X-ray fluorescence spectrometry (XRF) and inductively coupled plasma mass spectrometry (ICP-MS). The chondrite-normalized rare earth element (REE) pattern shows an increase in light REEs (LaN/SmN, 0.93–4.03; average 2.24), negligible negative Eu anomalies (Eu/Eu*, 0.68–1.11; average 0.85), and relatively flat heavy REEs (GdN/YbN, 0.47–2.30; average 1.4). The chemical indices, such as the chemical index of alteration, plagioclase index of alteration, and chemical index of weathering, as well as the ratios of K2O/Al2O3, Rb/Sr, Th/U, and the A-CN-K (Al2O3-(CaO*+Na2O)-K2O) ternary plot, indicate that the source area of the metasedimentary rocks has undergone moderate to intense chemical weathering. The ratios of Al2O3/TiO2, La/Sc, Th/Sc, La/Co, Th/Co, and Th/U, as well as the A-CN-K ternary plot, suggest that the protoliths of the metasedimentary rocks originated from a combination of mafic and felsic igneous sources. Additionally, the Th/Sc, Zr/Sc, and SiO2/Al2O3 ratios, along with the index of compositional variation, indicate that the metasedimentary rocks were derived from a mixture of immature mafic and felsic igneous sources, first-cycle sediments with minimal recycled components. The discrimination diagrams of La-Th-Sc and Th-Sc-Zr/10 suggest that the Mai Kenetal-Werii metasedimentary rocks were deposited in an oceanic island arc setting.