Background: Combined with the increasing life expectancy, chronic medical conditions have gradually become the dominant cause of death and disability, and multimorbidity became an increasingly serious public health challenge. However, most existing studies have focused on the coexistence of specific diseases or relatively few diseases. Given one person may have multiple diseases at the same time, we applied Charlson Comorbidity Index (CCI) to systematically evaluate one's 10-year mortality. In this study, we explored the effects of nutrients and physical activity on CCI using National Health and Nutrition Examination Survey (NHANES) 2013-2014 data. Methods: The study sample consists of one continuous cycle (2013-2014) of NHANES, and 4386 subjects were included in the study. Nutrients intake was measured by dietary recall, and physical activity was evaluated by the Global Physical Activity Questionnaire respectively. Besides, CCI was the sum of the scores assigned for each medical condition. We utilized zero-inflated negative binomial (ZINB) model to investigate the effects in nutrients intake and physical activity on CCI by adjusting for seven sociodemographic characteristics, smoking and drinking. Results: Among the 4386 participants, 2018 (68.7%) are Non-Hispanic White, over half participants (78.6%) drink. In count part (CCI ≥ 0), holding other variables constant, the expected change in CCI for a one-unit increase in niacin is 1.621(RR = 1.621, p = 0.016), in lutein + zeaxanthin is 0.974 (RR = 0.974, p = 0.031), and in sedentary time is 1.035 (RR = 1.035, p = 0.005). Moreover, those who do not have vigorous work activity would be more likely to have higher CCI than those who have (RR = 1.275, P = 0.045). In logit part (CCI = 0), the log odds of having CCI equals zero would increase by 0.541 and 0.708 for every additional vigorous recreational activity (OR = 0.541, p = 0.004) and moderate recreational activity (OR = 0.708, p = 0.017) respectively. Conclusions: Lutein and zeaxanthin intake, vigorous work activity, vigorous recreational activity and moderate recreational activity may be good for one's health. Rather, increasing niacin intake and sedentary activity may be likely to raise 10-year mortality. Our findings may be significant for preventing diseases and improving health, furthermore, reducing people's financial burden on healthcare.