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Abstract Background Relative handgrip strength (RHGS) was positively correlated with healthy levels of cardiovascular markers and negatively correlated with metabolic disease risk. However, its association with hyperlipidemia remains unknown. The present study investigated the link between RHGS and hyperlipidemia, utilizing data from the National Health and Nutrition Examination Survey (NHANES) and further examined the hypothesis that inflammation may serve a mediating role within this relationship. Methods Data were extracted from 4610 participants in the NHANES database spanning 2011–2014 to explore the correlation between RHGS and hyperlipidemia using multivariate logistic regression models. Subgroup analyses were conducted to discern the correlation between RHGS and hyperlipidemia across diverse populations. Additionally, smooth curve fitting and threshold effect analysis were conducted to validate the association between RHGS and hyperlipidemia. Furthermore, the potential mediating effect of inflammation on this association was also explored. Results According to the fully adjusted model, RHGS was negatively correlated with hyperlipidemia [odds ratio (OR) = 0.575, 95% confidence interval (CI) = 0.515 to 0.643], which was consistently significant across all populations, notably among women. Smooth curve fitting and threshold effect analysis substantiated the negative association between RHGS and hyperlipidemia. Moreover, the mediating effects analysis indicated the white blood cell (WBC) count, neutrophil (Neu) count, and lymphocyte (Lym) count played roles as the mediators, with mediation ratios of 7.0%, 4.3%, and 5.0%, respectively. Conclusions This study identified a prominent negative correlation between RHGS and hyperlipidemia. Elevated RHGS may serve as a protective factor against hyperlipidemia, potentially through mechanisms underlying the modulation of inflammatory processes.