To meet the growing demand for high‐oleic soybean [Glycine max (L.) Merr.] cultivars, the University of Missouri‐Fisher Delta Research, Extension, and Education Center soybean breeding program has developed and released ‘S16‐16641R’ (Reg. no. CV‐559, PI 703070). It is a productive maturity group 4‐late (relative maturity 4.8), glyphosate‐tolerant (Roundup Ready 1) cultivar with high‐oleic content (81.7%) and reduced linolenic acid content (4.3%). In addition to its high‐yield potential, S16‐16641R has a broad disease resistance including soybean cyst nematode (Heterodera glycines Ichinohe) races 1 (HG Type 2.5.7), 2 (HG Type 1.2.5.7), 3 (HG Type 5.7), and 5 (HG Type 2.5.7), southern root‐knot nematode [Meloidogyne incognita (Kofoid and White) Chitwood], reniform nematode (Rotylenchulus reniformis Linford & Oliveira), and stem canker (caused by Diaporthe aspalathi Jansen, Castlebury & Crous). It is a chloride excluder with tolerance to high salt field conditions. It was tested in 43 environments across eight states from 2017 to 2020, with an overall relative yield of 99.9% of the mean of the check. The high‐oleic acid content and comprehensive disease resistance combined with broad adaptability and high yield potential across multiple environments make S16‐16641R a promising soybean cultivar for growers to potentially maximize profits by receiving a premium price for high‐oleic oil content.