In recent years, Unmanned Aerial Systems (UAS) have emerged as an innovative technology to provide spatio-temporal information about weed species in crop fields. Such information is a critical input for any site-specific weed management program. A multi-rotor UAS (Phantom 4) equipped with an RGB sensor was used to collect imagery in three bands (Red, Green, and Blue; 0.8 cm/pixel resolution) with the objectives of (a) mapping weeds in cotton and (b) determining the relationship between image-based weed coverage and ground-based weed densities. For weed mapping, three different weed density levels (high, medium, and low) were established for a mix of different weed species, with three replications. To determine weed densities through ground truthing, five quadrats (1 m × 1 m) were laid out in each plot. The aerial imageries were preprocessed and subjected to Hough transformation to delineate cotton rows. Following the separation of inter-row vegetation from crop rows, a multi-level classification coupled with machine learning algorithms were used to distinguish intra-row weeds from cotton. Overall, accuracy levels of 89.16%, 85.83%, and 83.33% and kappa values of 0.84, 0.79, and 0.75 were achieved for detecting weed occurrence in high, medium, and low density plots, respectively. Further, ground-truthing based overall weed density values were fairly correlated (r² = 0.80) with image-based weed coverage assessments. Among the specific weed species evaluated, Palmer amaranth (Amaranthus palmeri S. Watson) showed the highest correlation (r² = 0.91) followed by red sprangletop (Leptochloa mucronata Michx) (r² = 0.88). The results highlight the utility of UAS-borne RGB imagery for weed mapping and density estimation in cotton for precision weed management.