Soil degradation (SD) poses a significant challenge to tropical agricultural production systems due to its role in depleting soil nutrients. Recently, SD has threatened population growth by causing hunger and poverty among smallholder farmers in the Guinea savanna agro-ecological zone of Ghana. However, SD cannot be directly measured. Instead, assessment and modelling efforts rely on biological and physico-chemical indicators. This study sought to: (i) select a minimum dataset (MDS) using a multivariate statistical technique; (ii) identify SD processes, and evaluate the extent of degradation; and (iii) suggest strategies to monitor SD in the study area. Soil samples were collected using the Land Degradation Surveillance Framework (LDSF), specifically designed for sub-plot level (1000 m2) sampling. This scheme aligns well with the typical farm structure of smallholder farmers (<10 acres). Soil samples, taken from a depth of 0–20 cm, were analyzed to assess their physico-chemical properties. Principal component analysis (PCA) identified seven key SD processes: soil texture, pH, organic carbon (OC), total nitrogen (TN), available phosphorus (Av. P), base saturation (BS) and Effective Cation Exchange Capacity (ECEC). These identified processes lead to the loss of OC, deterioration of soil texture, reduction in soil nutrients, and increased soil acidity. There was a strong positive correlation (r = 0.70, p<0.05) between soil physical and chemical properties. PC1 explained 26.86% of the total variance, followed by PC2 at 15.31%, PC3 at 12.46%, and PC4 at 9.98%. Also, PC5, PC6, and PC7 accounted for 8.49%, 7.25% and 1.42% of the variance, respectively. The land-use systems we identified significantly affected the concentration of soil nutrients (p<0.001). In our computed Composite Soil Degradation Index (CSDI), CEC emerged as the most significant SD indicator with a weight of 0.328, followed by Si:CL ratio at 0.187. The results indicate that soil management activities should focus on increasing organic matter. Soil nutrient depletion primarily occurs through several processes. Land clearing and burning of organic materials during land preparation are primary causes. Furthermore, a total crop removal during harvest, inadequate manure application, and subsequent leaching and erosion aggravates SD, leading to nutrient-depleted soils. We conclude that the loss of nutrients, specifically CEC, OC, Ex. K and Av. P is the primary contributor to chemical SD. Therefore, implementing integrated soil fertility management (ISFM) strategies, such as applying organic (e.g., animal-based manures, green manure, crop residues, compost) and inorganic fertilizers (e.g., NPK + micronutrients) is crucial for increasing soil nutrient availability, enhancing SOM content, and promoting carbon sequestration in these farming systems. This study establishes a baseline for comparing and evaluating the effectiveness of land management interventions at the landscape level in northern Ghana. Consequently, soil nutrient management should be tailored to site-specific conditions, focusing on increasing the efficiency of N, P, K and micronutrient uptake by plants. Adopting such site-specific management strategies could significantly contribute to the sustainable intensification of agricultural production systems in the Guinea Savanna agro-ecological zone of Ghana.