In the past 20 years, weed control in soybean (Glycine max) was mainly based on postemergence (POST) applications of glyphosate, which resulted in glyphosate‐resistant weeds. Herbicide‐resistant weeds warrants evaluation of new strategies for effective control. Therefore, the objective of this study was to evaluate the performance of herbicides applied preemergence (PRE) and POST on 11 agronomic weeds in eastern Nebraska. The study was conducted in 2014 and 2015 in Concord, NE. The best PRE‐applied treatments were metolachlor + imazethapyr, fomesafen + imazethapyr, flumioxazin + imazethapyr, and flumioxazin + metribuzin, which controlled broadleaf and grass weed species ≥90 and ≥80%, respectively. However, weed control with POST herbicides was more variable, ranging from 19 to 91%. The POST‐applied fomesafen and fomesafen + imazethapyr controlled ivyleaf morningglory (Ipomoea hederacea), common lambsquarters (Chenopodium album), common waterhemp (Amaranthus tuberculatus), and redroot pigweed (Amaranthus retroflexus) ≥85%. Greater soybean yields were achieved with most PRE‐applied herbicides and POST‐applied fomesafen + imazethapyr only. Metolachlor + imazethapyr, metolachlor, and fomesafen applied PRE protected soybean yields better than when applied POST. Results suggested that PRE‐applied herbicide mixtures of different sites of action are the base for controlling weeds and protecting soybean yields in eastern Nebraska.