TikTok has swiftly risen to prominence as one of the world’s top social media and entertainment sites. Every day, millions of users log on to the site. The platform’s users generate millions of moments and post several videos every minute. Nevertheless, research shows that TikTok usage is more prevalent among those with high self-esteem and less among those with poor self-esteem. This study examines the relationship between TikTok usage, social comparison, and self-esteem using gender as a moderator. The research used a cross-sectional survey design in which structured questionnaires were used to collect data from a sample of 314 TikTok users among university students in Nigeria. Structural Equation Modeling-Analysis of Moment Structures (SEM- AMOS) was employed to test the study hypotheses. The results showed that TikTok usage has a positive and statistically significant direct effect on self-esteem with a path coefficient (Beta) =.330, (p = 0.000) and critical ratios (z-values) = 3.402. Additionally, the study revealed that social comparison has statistically significant effects on self-esteem with a path coefficient (Beta) =.570, p = 0.000, and critical ratios (z-values) = 7.870. However, the result of moderating analysis shows that the effect is more pronounced in the female group than in the male group. The study provides empirical evidence on the moderating role of gender in the relationship between TikTok usage, social comparison, and self-esteem among Nigerian university students.