Plasma neurofilament light (NfL) protein is a promising non-invasive biomarker for detecting neuronal damage in Alzheimer's disease (AD). However, its clinical utility is limited by the lack of standardized threshold values. Sex is an important factor that should be considered when setting these thresholds, but only a few studies have examined sex differences in plasma NfL levels in AD, with inconsistent findings. Even fewer have explored whether sex influences the relationship between plasma NfL levels and disease severity. To investigate this, we first analyzed data from 860 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Linear regression models were used to assess sex differences in the correlation between plasma NfL levels, cognitive deficits, and neuroimaging metrics. A Cox model with bootstrap resampling was used to evaluate sex differences in dementia risk, calculating the hazard ratio for men versus women for a given increase in plasma NfL. Our results showed that, compared to women, men with higher plasma NfL levels exhibited more severe cognitive defects and brain hypometabolism, along with smaller hippocampal volume. These findings were validated using data from 619 participants in the Chinese Preclinical Alzheimer's Disease Study (C-PAS) cohort and 86 participants from a publicly available dataset. In addition, we found that increase in plasma NfL levels were predictive of faster cognitive decline and a higher likelihood of AD progression in men compared to women. In conclusion, sex differences influence the relationship between plasma NfL levels and AD symptoms. Men exhibit greater cognitive and neuropathological defects with rising plasma NfL levels, underscoring the need for considering sex when using NfL as a biomarker for neuronal damage in AD.