Objective: Given lycopene's anti-inflammatory and antioxidant properties, we investigated its mortality impact in individuals with and without obesity, confirming distinct effects. Methods: This study analyzes the National Health and Nutrition Examination Survey (NHANES) data from 2003-2006 and 2017-2018, linking lycopene levels to all-cause and cardiovascular mortality. Using various statistical methods, three models are sequentially adjusted for confounders, investigating the lycopene-outcome relationship. Results: We studied 11 737 adults for 162 months and found 1537 all-cause deaths (13.1%) and 443 cardiovascular deaths (3.8%). For those without obesity, serum lycopene had an "L" shape relationship with all-cause mortality, being harmful at very low levels but protective above a certain threshold. It consistently protects against cardiovascular mortality. In individuals with obesity, the relationship with all-cause mortality formed a "U" shape, with increased risk at very low and very high lycopene levels and protection in the middle range. Cardiovascular mortality showed a similar pattern in individuals with obesity. Interestingly, dietary lycopene intake had protective effects in both groups. Conclusion: This study reveals that lycopene exhibits distinct associations with all-cause and cardiovascular mortality in populations with or without obesity, emphasizing the importance of considering individual health profiles when assessing its benefits.