Research shows that learning enjoyment in specific socio-scientific issues (SSI) plays an important role in predicting grade 10 students’ learning interest and learning enjoyment (i.e., genuine interest) in SSI subjects generally. However, it remains unexplored whether learning enjoyment also mediates a predictive effect of learning interest in a Big Science SSI of pressing contemporary global concern—COVID-19—on grade 12 high school students’ learning interest in SSI generally. The purpose of this study is to investigate how learning enjoyment may mediate the predictive effect of learning interest in the specific Big Science SSI of COVID-19 specifically on students’ learning interest in SSI subjects generally. Latent variable modeling using data collected from grade 12 students (N = 691) showed personal perceptions of learning enjoyment in SSI partially mediated the predictive effect of learning interest in the SSI of COVID-19 on learning interest in other Big Science SSI subjects. Implications for promoting among science educators and policy specialists the active development of students’ individual interests and involvement in other 21st century Big Science SSI challenges are forwarded.