The new generation of Chinese rural-to-urban migrants, who were born after the 1980s, has played an increasingly significant role in the development of China. This paper explores the correlations between interpersonal trust and health-related quality of life (HRQOL) of Chinese rural-to-urban migrants by comparing two generations. A survey (N = 769) was conducted on rural-to-urban migrants in Wuhan in 2012. Significant differences between the two generations emerged in terms of education, working hours, and other factors. First-generation migrants reported a higher level of trust in family, relatives, and neighbors compared with new-generation migrants. The new generation had better physical health and worse mental health. Confirmatory factor analysis and structural equation model were employed. Results indicated that the new generation obtained more path coefficients that passed the significance tests; that is, interpersonal trust obtained more significant correlations with the new generation. The coefficient between workmate trust and vitality among new-generation migrants was the largest (5.293, P < 0.001), whereas the coefficient between family trust and vitality among first-generation migrants was the smallest (1.639, P < 0.05). The correlations between the six domains of interpersonal trust and HRQOL were balanced. The different backgrounds in upbringing, occupational and living conditions, changed values, and psychological characteristics were associated with these. This study highlighted the need to address the psychological concerns, treatment, and intervention of the new generation of Chinese rural-to-urban migrants.