Fungal endophytes are an emerging source of novel traits and biomolecules suitable for lignocellulosic biomass treatment. This work documents the toxicity tolerance of Colletotrichum sp. OH toward various lignocellulosic pretreatment-derived inhibitors. The effects of aldehydes (vanillin, p-hydroxybenzaldehyde, furfural, 5-hydroxymethylfurfural; HMF), acids (gallic, formic, levulinic, and p-hydroxybenzoic acid), phenolics (hydroquinone, p-coumaric acid), and two pretreatment chemicals (hydrogen peroxide and ionic liquid), on the mycelium growth, biomass accumulation, and lignocellulolytic enzyme activities, were tested. The reported Colletotrichum sp. OH was naturally tolerant to high concentrations of single inhibitors like HMF (IC50; 17.5 mM), levulinic acid (IC50; 29.7 mM), hydroquinone (IC50; 10.76 mM), and H2O2 (IC50; 50 mM). The lignocellulolytic enzymes displayed a wide range of single and mixed inhibitor tolerance profiles. The enzymes β-glucosidase and endoglucanase showed H2O2- and HMF-dependent activity enhancements. The enzyme β-glucosidase activity was 34% higher in 75 mM and retained 20% activity in 125 mM H2O2. Further, β-glucosidase activity increased to 24 and 32% in the presence of 17.76 and 8.8 mM HMF. This research suggests that the Colletotrichum sp. OH, or its enzymes, can be used to pretreat plant biomass, hydrolyze it, and remove inhibitory by-products.