Since the 1950s, The Greater Cairo Metropolitan Region (GCMR) has experienced an unprecedented rate of informal urbanization over productive arable lands, forming fragmented landscape and accompanied with significant socioeconomic influences. Recent data show that 62% of Greater Cairo and 87% of Giza are informal settlements resulting from urban sprawl, with 80% of these informal settlements built on privately owned agriculture lands. Beside the direct loss of agricultural land, the fragmented agricultural lands, created by urban expansion, road networks, and constructions, suffers from indirect impacts on the inputs of agricultural processes, such as increased irrigation requirements, soil contamination. This study aims to develop a conceptual framework illustrating the interrelationship between urban sprawl and agricultural activities through a case study on one district (Tersa District) in the Giza governorate. The study implemented both qualitative and quantitative data collection techniques as well as water samples analysis. Data were collected through structured questionnaires and in-depth interviews with 30 farmers, 50 residents, and governmental authorities to investigate changes in the different facets of agricultural activities over a 10-year period from 2007 to 2017. Changes in agricultural activities were assessed in terms of changes in cultivated land ownership, agricultural laborers, agricultural cooperative organization support to farmers, crop type, and livestock management activities. To evaluate the possible impact of urban sprawl on water quality, water samples in four locations were analyzed. The research affirms that urban sprawl has led to loss of about 19% of Tersa’s fertile agricultural lands between 2007 and 2017 and revealed many challenges facing farmers in the remaining fragmented lands due to urban sprawl, including polluted irrigation water, diminishing soil fertility, increased labor wages, reduction of institutional support, and alteration of crop type. The similarity of these challenges with other challenges identified in the international literature provided the needed background to propose a framework exploring the interrelationship between urban sprawl and agricultural activities. This framework can highlight entry points for various interventions to ameliorate and address the negative impact of urban sprawl in remaining agricultural areas. In addition to the most foremost intervention of intensifying efforts to control urban sprawl, ensuring sustained good quality of irrigation water, efficient institutional support, and building channels of communication and trust among members of the communities can support the sustainability of agricultural activities and enhance food security in these areas.