The study aimed to discuss the association between sleep duration and the risk of hyperhomocysteinemia (Hhcy). This cross-sectional study included 4173 adults (≥ 20 years) from the National Health and Nutrition Examination Survey 2005-2006. According to their sleep duration, participants were divided into five subgroups. Multivariate logistic regression analysis models and restrictive cubic spline regressions were used to explore the association between sleep duration and the risk of Hhcy. Compared with the participants who sleep 7 h, sleep deprivation (≤ 5 h) increased the risk of Hhcy, odds ratio (OR) 1.68 (95% confidence interval (CI) 1.06-2.68); Excessive sleep (≥ 9 h) also increased the risk of Hhcy, OR 1.86 (95% CI 1.09-3.14) after adjusting for a series of confounding factors in the entire population. The risk of Hhcy was distributed in a U-shape with sleep duration. Similar results were demonstrated in obese populations. The association between sleep duration and the risk of Hhcy is U-shaped. Both sleep deprivation and excessive sleep can increase the risk of Hhcy.