Background <p>Previous studies have established an association between age-related macular degeneration (AMD) and chronic systemic inflammation. However, the relationship between AMD and the monocyte-to-lymphocyte ratio (MLR), a novel inflammatory biomarker, remains unclear. In this study, we aimed to investigate the association between MLR and AMD using data from the 2005–2008 National Health and Nutrition Examination Survey (NHANES).</p> Methods <p>Data from three NHANES cycles (2005–2008) were analyzed to preliminarily assess the association between MLR and AMD, excluding participants with incomplete data. We utilized weighted logistic regression models, restricted cubic spline functions (RCS) and constructed receiver operating characteristic (ROC) curves to evaluate the association between MLR and AMD.</p> Results <p>A total of 4,894 participants were deemed eligible for our analysis, with 379 individuals diagnosed with AMD. The Monocyte to Lymphocyte Ratio (MLR) was significantly elevated in the AMD group compared to the non-AMD group. After adjusting for potential confounding factors, we found that elevated MLR levels were significantly associated with an increased risk of AMD, with an OR of 2.56, 95% CI: (1.17,5.58), <i>P</i> = 0.022. The restricted cubic spline (RCS) analysis revealed a significant nonlinear relationship between MLR and AMD, with an inflection point at 0.26 (nonlinear <i>P</i> &lt; 0.05). Furthermore, the receiver operating characteristic (ROC) curve analysis demonstrated that MLR exhibited acceptable discrimination for AMD.</p> Conclusions <p>Elevated MLR is associated with an increased risk of AMD, suggesting that MLR may serve as a simple and effective clinical biomarker of AMD.</p>