This study aimed to assess the effects of fluoridated varnishes supplemented with micrometric or nanosized sodium trimetaphosphate (TMPmicro or TMPnano, respectively) against enamel softening in an early erosive model in vitro. Bovine enamel blocks (with mean surface hardness [SH] between 330.0 and 380.0 kgf/mm2) were selected and randomly assigned according to their SH (n = 8) into the following groups: Placebo (no fluoride/TMP; negative control), 5% NaF (positive control), 5% NaF + 5%TMPmicro, 5% NaF + 2.5%TMPnano and 5% NaF + 5%TMPnano. Blocks received a single application of the varnishes and were immersed in artificial saliva (6 h). Thereafter, the varnishes were removed and the blocks were subjected to four individual erosive challenges (1 min, citric acid, 0.75%, pH = 3.5, under agitation); SH was determined after each challenge. Data were subjected to ANOVA and Student–Newman–Keuls’ test (p < 0.05). Overall, the highest %SH loss was observed for the Placebo, followed by 5% NaF, 5% NaF + 5% TMPmicro, and both varnishes containing TMPnano, without significant differences between 2.5% and 5% TMPnano. It was concluded that TMP enhanced the effects of a 5% NaF varnish against enamel softening in an early erosive model in vitro, with an additional benefit from the use of nanoparticles over microparticles.