The objective of this research was to explore the influence that weed decision threshold (DT; expressed as plants m−2), weed spatial distribution patterns, and spatial resolution of sampling have on potential reduction in herbicide use under site-specific weed management. As a case study, a small plot located in a typical corn field in central Spain was used, constructing very precise distribution maps of the major weeds present. These initial maps were used to generate herbicide prescription maps for each weed species based on different DTs and sampling resolutions. The simulation of herbicide prescription maps consisted of on/off spraying decisions based on information from two different approaches for weed detection: ground-based vs. aerial sensors. In general, simulations based on ground sensors resulted in higher herbicide savings than those based on aerial sensors. The extent of herbicide reductions derived from patch spraying was directly related to the density and the spatial distribution of each weed species. Herbicide savings were potentially high (up to 66%) with relatively sparse patchy weed species (e.g., johnsongrass) but were only moderate (10 to 20%) with abundant and regularly distributed weed species (e.g., velvetleaf). However, DT has proven to be a key factor, with higher DTs resulting in reductions in herbicide use for all the weed species and all sampling procedures and resolutions. Moreover, increasing DT from 6 to 12 plants m−2 resulted in additional herbicide savings of up to 50% in the simulations for johnsongrass and up to 28% savings in the simulations for common cocklebur. Nonetheless, since DT determines the accuracy of patch spraying, the consequences of using higher DTs could be leaving areas unsprayed, which could adversely affect crop yields and future weed infestations, including herbicide-resistant weeds. Considering that the relationship between DT and accuracy of herbicide application depends on weed spatial pattern, this work has demonstrated the possibility of using higher DT values in weeds with a clear patchy distribution compared with weeds distributed regularly.