To compare first- and second-immigrant pediatric populations with a non-immigrant pediatric population in terms of quality-of-life metrics, a cross-sectional analysis using data from the DIATROFI Program was implemented. In total, n = 2277 students (mean age: 9(4) years) from public schools in Greece participating in the 2020–2021 school year were analyzed. The students’ immigration status (first-generation/second-generation) was defined as per the standard definition. The students’ health related-quality of life (HRQoL) was assessed using a parental-perceived quality of life questionnaire. The sample included 4.8% first-generation and 21.2% second-generation immigrant students. Compared with non-immigrants, the first-generation immigrant students were more likely to have poor HRQoL (odds ratio (OR) = 2.82; 95% confidence interval (95%CI) = 11.75, 4.53), physical (OR = 1.91; 95%CI = 1.18, 3.10), social (OR = 1.94; 95%CI = 1.16, 3.22) and school function (OR = 2.52; 95%CI = 1.54, 4.13). Similar results were observed for second-generation immigrant students regarding HRQoL (OR = 1.68; 95%CI = 1.28, 2.21), physical (OR = 1.60; 95%CI = 1.23, 2.10) and school function (OR = 2.09; 95%CI = 1.58, 2.77). Children with one parent having a country of origin different that the country of residence had elevated odds of having poor emotional health (OR = 1.19; 95%CI = 0.87, 1.64). The family’s affluency level was interrelated with the connection of poor HRQoL and immigration status. The immigrant students have a poorer quality of life depending on their immigration generation and irrespective of their socioeconomic background.