Lack of precipitation and groundwater for irrigation limits crop production in semi-arid regions, such as the Southern High Plains (SHP). Advanced technologies, such as variable rate irrigation (VRI), can conserve water and improve water use efficiency for sustainable agriculture. However, the adoption of VRI is hindered by the lack of on-farm research focusing on the feasibility of VRI. The objective of this study was to assess the effect of irrigation rates on cotton yield as affected by soil physical properties and topography in the Southern High Plains. This study was conducted in two fields within a 194-ha commercially managed farm in Hale County, Texas, in 2017. An irrigation treatment with three rates was implemented in a randomized complete block design with two replications as separate blocks in each field. A total of 230 composite soil samples were collected from the farm in spring 2017 and analyzed for texture. Information on apparent soil electrical conductivity (ECa), elevation, and final yield were collected from the fields. A statistical model showed that the effect of irrigation rates on cotton yield depended on its interaction with soil physical properties and topography. For example, areas with slope >2% and sand content >50% had no significant response to higher irrigation rates. This model suggests that applying irrigation amounts based on the yield response can be a basis for VRI. This study provides valuable information for site-specific irrigation to optimize crop production in fields with significant variability in soil physical properties and topography.