Italian ryegrass (Lolium perenne ssp. multiflorum (Lam) Husnot) is a troublesome weed species in wheat (Triticum aestivum) production in the United States, severely affecting grain yields. Spatial mapping of ryegrass infestation in wheat fields and early prediction of its impact on yield can assist management decision making. In this study, unmanned aerial systems (UAS)-based red, green and blue (RGB) imageries acquired at an early wheat growth stage in two different experimental sites were used for developing predictive models. Deep neural networks (DNNs) coupled with an extensive feature selection method were used to detect ryegrass in wheat and estimate ryegrass canopy coverage. Predictive models were developed by regressing early-season ryegrass canopy coverage (%) with end-of-season (at wheat maturity) biomass and seed yield of ryegrass, as well as biomass and grain yield reduction (%) of wheat. Italian ryegrass was detected with high accuracy (precision = 95.44 ± 4.27%, recall = 95.48 ± 5.05%, F-score = 95.56 ± 4.11%) using the best model which included four features: hue, saturation, excess green index, and visible atmospheric resistant index. End-of-season ryegrass biomass was predicted with high accuracy (R² = 0.87), whereas the other variables had moderate to high accuracy levels (R² values of 0.74 for ryegrass seed yield, 0.73 for wheat biomass reduction, and 0.69 for wheat grain yield reduction). The methodology demonstrated in the current study shows great potential for mapping and quantifying ryegrass infestation and predicting its competitive response in wheat, allowing for timely management decisions.