Yerba mate consumption has been stimulated by scientific discoveries that have identified high concentrations of bioactive compounds and their health benefits. We were interested in quantifying caffeine, theobromine, total phenolic compounds and protein concentrations in yerba mate genotypes and their stability over four years on the same plants. Mature leaves from adult yerba mate genotypes selected on a provenance and progenies trial were collected in August of 2015, 2016, 2017 and 2018. Methylxanthines (caffeine and theobromine) were quantified by High-Performance Liquid Chromatography (HPLC), total phenolic compounds by Folin–Ciocalteau spectrophotometric method and total protein analysis by the micro-Kjeldahl method. Genotype stability was analyzed through the AMMI (Additive Main effects and Multiplicative Interaction) procedure. Our results indicate large variations between genotypes regarding caffeine (0.035 to 2.385 g 100 g−1), theobromine (0.0004 to 1.772 g 100 g−1), total phenolic compounds (7.028 to 9.424 g 100 g−1), proteins (10.39 to 16.58 g 100 g−1) contents and the high stability of those compounds over the four evaluated years, on the same plants. This information, combined with the stability of bioactive compounds, establishes a significant potential for innovation within the Ilex paraguariensis species.