<p>To assess whether estimated dietary microplastic (MP) intake is linked to age-standardized lip and oral cavity cancer rates at the country level, independent of smoking, alcohol, socioeconomic status, and urbanization, we conducted a cross-sectional ecological study across 106 countries (2020 anchor year). While testing for effect modification by smoking, dietary MP intake showed a non-linear association with lip–oral cavity cancer incidence in unadjusted spline models. Smoking prevalence and urbanization were also positive predictors, although the evidence was inconsistent. Placebo/permutation testing, spatial residual diagnostics, and dietary-structure sensitivity analysis using fish/seafood supply as a proxy supported the stability and specificity of the association. We additionally performed a pre-specified spatial econometric sensitivity analysis: residual Moran’s I on the refitted OLS model (<i>n</i> = 79) was 0.099 (p_sim = 0.082); Anselin’s robust LM-lag test was significant (<i>p</i> = 0.003), identifying a Spatial Lag Model (SLM) as the appropriate primary spatial specification (ρ = 0.35; post-fit Moran’s I = − 0.006, p_sim = 0.466 autocorrelation absorbed). Under SLM, the MP p90-vs-p10 exposure contrast was − 0.41 (<i>p</i> = 0.85); the pre-specified decision rule thereby classifies this result as null/hypothesis-generating (Path C). These findings generate hypotheses and do not establish causality, but encourage further individual-level exposure assessments and mechanistic studies to better understand the potential role of microplastics in oral carcinogenesis.</p>