In the semi-arid Southern High Plains of the U.S., intensively-tilled, low-residue monoculture cotton cropping has been the primary agricultural practice since the 1940s.   A consequence of this is that soil organic matter in the sandy soils of this region, already inherently low, has become further depleted, resulting in soils with reduced water-holding capacity that are prone to aeolian erosion.  Although alternative cropping options are limited in this region due to climate constraints and the limited irrigation capacity of the depleted Ogallala aquifer, drought tolerant, high-residue crops such as sorghum offer viable alternative cropping systems that are both economically and environmentally beneficial.  This study evaluated the short-term changes in soil functioning related to a transition from cotton to sorghum cropping systems using a suite of five soil enzyme assays targeting soil C (β-Glucosidase), N (β-Glucosaminidase), P (Alkaline Phosphatase, Phosphodiesterase) and S (Arylsulfatase) cycling.  Specifically we investigated 2 high-tonnage yield forage sorghum cultivars with different cell wall composition (typical and reduced lignin content) under 2 deficit irrigation levels (rain-fed non irrigated and supplemental irrigation at 2.88 mm day^-1) and 2 biomass removal rates (100% and 50% removal).  Soil sampling (0-10 cm) was conducted in 2008 (prior to study initiation) and repeated in 2009 and 2010. After 2 years under sorghum, all five soil enzyme activities had increased 25-38% compared to baseline soil.  Certain enzyme activities (β-Glucosidase, Alkaline Phosphatase, Phosphodiesterase) were higher (16-19%) under irrigated sorghum compared to non-irrigated.  However, no differences were detected due to sorghum cultivar or the amount of biomass removed.  This study demonstrated that soil enzyme activities are sensitive indicators to short-term changes in cropping systems and that positive responses were detected in a 2-year transition from cotton to a high-tonnage forage sorghum system, regardless of irrigation water level, % aboveground biomass incorporated into soil, and sorghum cultivar.