Herbicides are critical resources for meeting agricultural demand. While similar in structure and function to pharmaceuticals, the development of new herbicidal mechanisms of action and new scaffolds against known mechanisms of action has been much slower than in pharmaceutical sciences. We hypothesized that this may be due in part to a relative undersampling of possible herbicidal chemistries and set out to test whether this difference in sampling existed and whether increasing the diversity of possible herbicidal chemistries would be likely to result in more efficacious herbicides. To conduct this work, we first identified databases of commercially available herbicides and clinically approved pharmaceuticals. Using these databases, we created a two-dimensional embedding of the chemical, which provides a qualitative visualization of the degree to which each chemotype is distributed within the combined chemical space and shows a moderate degree of overlap between the two sets. Next, we trained several machine learning models to classify herbicides versus drugs based on physicochemical characteristics. The most accurate of these models has an accuracy of 93% with the key differentiating characteristics being the number of polar hydrogens, number of amide bonds, LogP, and polar surface area. We then used several types of scaffold decomposition to quantitatively evaluate the chemical diversity of each molecular family and showed herbicides to have considerably fewer unique structural fragments. Finally, we used molecular docking as an in silico evaluation of further structural diversification in herbicide development. To this end, we identified herbicides with well-characterized binding sites and modified those scaffolds based on similar structural subunits from the drug dataset not present in any commercial herbicide while using the machine-learned model to ensure that required herbicide properties were maintained. Redocking the original and modified scaffolds of several herbicides showed that even this simple design strategy is capable of yielding new molecules with higher predicted affinity for the target enzymes. Overall, we show that herbicides are distinct from drugs based on physicochemical properties but less diverse in their chemistry in a way not governed by these properties. We also demonstrate in silico that increasing the diversity of herbicide scaffolds has the potential to increase potency, potentially reducing the amount needed in agricultural practice.