The influence of circulating white blood cells and inflammatory factors on pruritus is gradually recognized by the public, but the specific causal relationship is still unknown. In this study, we included inflammatory cytokine profiles from 8293 healthy subjects, genetic data on blood cells from various ethnic and ancestry backgrounds, including 746,667 individuals, and 1370 patients of European descent with pruritus for a bidirectional 2-sample Mendelian randomization (MR) analysis. We employed several robust statistical methods, including the inverse variance weighted, weighted median, and the MR-Egger method. We further refined our analysis through a meticulous sensitivity assessment using the leave-one-out strategy, evaluated the heterogeneity of our findings using Cochran's Q test, and addressed potential pleiotropic effects through the MR-Egger intercept test. Ultimately, a reverse MR analysis was conducted to assess the potential for reverse causation. Genetic prediction data indicate a positive correlation between eosinophil cell count and the risk of developing pruritus (odds ratio [OR] = 1.31, 95% confidence interval [CI] = 1.09-1.55, P = .003). Furthermore, elevated levels of stromal-cell-derived factor 1 alpha (OR = 1.80, 95% CI: 1.15-2.77, P = .009), monokine induced by gamma interferon (OR = 1.23, 95% CI: 1.04-1.46, P = .015), and cutaneous T-cell-attracting chemokine (OR = 1.24, 95% CI: 1.01-1.53, P = .043) are all associated with an increased risk of pruritus occurrence, respectively. No evidence of horizontal pleiotropy or heterogeneity was observed among the genetic variants (P > .05), and the leave-one-out analysis confirmed the stability and robustness of this association. The reverse MR analysis demonstrated the absence of reverse causality. Our research delineates the causal links between eosinophil cell count, stromal-cell-derived factor 1 alpha, monokine induced by gamma interferon, cutaneous T-cell-attracting chemokine levels, and pruritus susceptibility. These insights may present promising avenues for enhancing the management and therapeutic strategies for patients suffering from pruritus.