Lake sediments can act as both sinks and secondary sources of toxic trace elements, posing potential ecological and human health risks in arid and semi-arid regions where hydrological connectivity, evaporation, and water-resource regulation strongly influence contaminant retention. In this study, 25 representative lakes in Inner Mongolia, northern China, were investigated to evaluate mercury (Hg) and arsenic (As) contamination in surface sediments collected during 2019–2023. A multi-index assessment framework integrating hierarchical cluster analysis, principal component analysis, the geo-accumulation index, an adjusted potential ecological risk index, one-way ANOVA, and a human health risk model was applied to identify Hg–As enrichment groups and assess associated risks. Hg and As concentrations ranged from 0.004 to 0.247 mg kg−1 and from 0.390 to 24.2 mg kg−1, respectively. Hierarchical cluster analysis identified a higher Hg–As enrichment group (L1) and a lower Hg–As enrichment group (L2), with L1 showing significantly higher concentrations, enrichment levels, and single-element ecological risk indices than L2. Hg was the dominant contributor to ecological risk because of its high toxic-response coefficient and enrichment relative to regional background values, whereas As contributed more strongly to the modeled non-carcinogenic health risk. The estimated hazard index for children was approximately 6.96 times that for adults under the assumed sediment-exposure scenario. Spatial risk differentiation was likely associated with the combined effects of agricultural drainage, coal-related emissions, artificial water diversion, terminal-lake retention, and sedimentary and hydrological processes. This study provides a regional-scale basis for identifying priority lakes and developing source- and pathway-specific management strategies for lake sediments in arid and semi-arid regions.