Land-use change (LUC) from natural to human-dominated land is a critical aspect of global change and ecosystem response. To improve our understanding of LUC, this study focused on: (1) developing a general theoretical framework for quantifying and evaluating the attributes of ecosystem response as a consequence of LUC; and (2) testing the validity of this framework using recent LUC in the desert fringe of the northern Negev Desert. Our framework is based on the premise that changes in soil and vegetation states are the most important and universal facets of ecosystems’ response to LUC. The framework depicts LUC as trajectories of indicators that signify soil and vegetation states, such as the soil quality index (SQI) and aboveground net primary productivity (ANPP), respectively, in a phase plane. The trajectories are characterized by both magnitude and the direction of the change that enable us to address and compare the general trends of the LUC. Our study explored the validity of the proposed framework for the following LUC cases: (1) grazing to natural ecosystem; (2) natural to grazing ecosystem; (3) rain-fed agricultural to natural ecosystem; and (4) rain-fed agricultural to grazing ecosystem. The SQI was quantified by 14 physical, biological, and chemical attributes that were merged into one index, while the ANPP was derived from biomass sampling. All transitions show strong relationships between SQI and ANPP (0.70 < R2 < 0.85; p < 0.05). Transitions from grazing to natural ecosystems are characterized by an increase in both SQI and ANPP variables; while all transitions that change from agricultural systems to less intensively managed systems, such as grazing or a natural system, show no change or a decrease in both SQI and ANPP. We infer that all the trajectories’ trends are a result of changes in the biodiversity dimensions during LUC. Analysis of the results revealed four properties of a theoretical framework that can be used for the developing science of LUC and ecosystem responses. Our framework enables: (1) a comparison between different types of LUC; (2) a study of transitions among self-organized and managed ecosystems; (3) the identification of short- and long-term effects; and (4) the integration of biodiversity and ecosystem function. We suggest that the four properties of the framework can provide the foundation for the development of an LUC science. However, the validity and the generality of the framework should be tested over a wide range of LUCs of terrestrial systems in the world.