To explore the effects of traditional Chinese medicine constitution (TCMC) on transformation of good health status to suboptimal health status (SHS), we conducted a nested case-control study among college students in China. During the 18-month mean follow-up time, 543 cases of SHS (42.7%) occurred in 1273 healthy students. There was a significant (P = 0.000) and marked reduction in SHMS V1.0 total score in the case group at the 18-month follow-up (69.32 ± 5.45) compared with baseline (78.60 ± 4.70), but there was no significant change in the control group. Conditional logistic regression analysis showed that respondents reporting Yin-deficiency and Qi-deficiency were, respectively, 2.247 and 2.198 times more likely to develop SHS, while tendency to Yin-deficiency and tendency to Damp-heat were, respectively, 1.642 and 1.506 times more likely to develop SHS. However, the Balanced Constitution was a significant protective factor (OR 0.649; P < 0.05). Altogether, these findings demonstrate that Yin-deficiency, Qi-deficiency, tendency to Yin-deficiency, and tendency to Damp-heat appeared to induce a change in health status to SHS, while the Balanced Constitution seemed to restrain this change. We conclude that regulating the unbalanced TCMC (such as Yin-deficiency and Qi-deficiency) may prevent a healthy status developing into SHS or lead to the regression of SHS.