This study aimed to comprehensively examine the relationship between science motivation and the 21st-century skill levels of secondary school students. The study was conducted according to the quantitative methodology using the correlational survey method. The convenience sampling approach was adopted in the study. The study group was analyzed in terms of gender and grade level variables. Additionally, the measurement models created for middle school students' "Science Motivation" (SM) and "21st-Century Skills" (21st-CS), as well as the theoretical structural model was created. The study included 507 secondary school students (252 females, 255 males). Based on the results of the study, reviewing SM scale and its sub-dimensions, there was no significant difference between genders in the dimensions except for "Intrinsic Motivation." In addition, a significant difference was found between the grade levels in terms of (SM) level. There was no significant difference in the different sub-dimensions of the 21st-CS according to gender; however, a significant difference was found in terms of grade levels. Generally, positive correlations were found between the sub-dimensions of the SM scale and the sub-dimensions of the 21st-CS levels. Additionally, there is a statistically significant relationship between science motivation and cognitive skill, affective skill, and socio-cultural skill. These findings emphasize that science education and motivation in this field may play a significant role in the development of 21st-CS.