Tire additives, extensively utilized as industrial raw materials, may enter aquatic environments through various pathways during production, usage, or disposal processes. Research has shown that these additives pose potential threats to human health. However, the information regarding human exposure to 1,3-diphenylguanidine (DPG), 1,3-di-o-tolylguanidine (DTG), and 1,2,3-triphenylguanidine (TPG) (collectively referred to as DPGs) remains limited. The objective of this research was to evaluate human exposure to DPG and its derivatives by analyzing urine and wastewater samples. DPG, DTG, and TPG were frequently detected in urine samples, with median concentrations of 0.19, 0.06, and 0.03 ng/L, respectively. The median urinary concentration of DPG was significantly higher in children than in the general population (p < 0.05). Nevertheless, higher concentrations of DPGs were detected in wastewater, with median values of 20.7 ng/L (DPG), 0.13 ng/L (DTG), and 0.85 ng/L (TPG). The per capita mass loads of ∑DPGs in wastewater treatment plants (WWTPs) were significantly higher on weekdays than weekends, whereas domestic WWTPs exhibited slightly lower average loads on weekdays compared to weekends. Additionally, urine–wastewater collaborative monitoring revealed that urinary excretion contributed only 28% to the total mass load of ∑DPGs in municipal wastewater, indicating it is not the main source in southern China. Consequently, the wastewater-based epidemiology (WBE) approach based on the analysis of parent compounds is unsuitable for assessing human exposure to DPGs. These results aid in developing an efficient surveillance system for understanding human exposure trends to DPGs.