Poor environmental technologies and gastrointestinal illnesses have been hypothesized to be a primary cause to the lack of impact of child health programs on child stunting rates (low height-for-age) in South Africa. This study assessed correlations between environmental exposures (water source, water treatment, sanitation, refuse), diarrheal occurrences, and systemic inflammation proxies among female and male children under five years of age in the Eastern Cape. A conceptual model was hypothesized using structural equation (SE) modeling and two sex-specific (female and male) datasets were subsequently generated from the data and applied to the hypothesized SE model. Results suggested that environmental exposure variables associated with diarrhea and systemic inflammation proxies were different between females and males. For diarrheal occurrences among females, an increase in local authority management of refuse (compared to household management) (0.161, p-value (p) = 0.007), sharing sanitation facilities (0.060, p = 0.023), and a decrease in the frequency of the treatment of drinking water (−0.043, p = 0.025) were correlated with an increase in diarrhea. For males, an increase in household use of flush toilets (as compared to ventilated pit latrines) was correlated with an increase in diarrhea (0.113, p = 0.027). For systemic inflammation among both sexes, an increase in household use of water pumped into the premises (as compared to a public water tap) and an increase in diarrheal occurrences were correlated with an increase in systemic inflammation. The data support an increased focus on sex and gender specific factors among field practitioners and policy makers working in the environmental health field in South Africa.