Mechanistic modeling of chemical transformations offers a compelling basis for understanding reactivity and allows for prediction of reaction outcomes before attempting experiments. Despite progress in machine-learned interatomic potentials (MLIPs), we demonstrate that available models lack the accuracy for diverse reaction modeling. With this motivation, we developed a general MLIP for mechanistic modeling of closed-shell carbon, hydrogen, nitrogen, and oxygen reactions, AIMNet2-rxn, using a dataset of ∼4.7 × 10 6 range-separated density functional theory calculations. AIMNet2-rxn enables reaction modeling ∼10 6 faster than the reference quantum mechanical (QM) methods while substantially outperforming graph-based ML, reaffirming the value using three-dimensional chemical information for training. On a test suite of well-known reaction mechanisms—such as amide formation, proton transfers, and pericyclics—AIMNet2-rxn yields 1 to 2 kilocalories per mole accuracy across reaction coordinates without retraining or system-specific fine-tuning. To exploit graphics processing unit parallelism and AIMNet2-rxn efficiency, we introduce a batched nudged elastic band procedure that readily achieves minimum energy pathway search on a millions-of-reactions scale. To demonstrate complex reaction characterization, the thermodynamics of an 11-step pathway producing hydroxymethylfurfural, the experimentally observed major product of glucose pyrolysis, is evaluated. Overall, the accuracy and efficiency afforded by AIMNet2-rxn create opportunities in high-throughput reaction discovery and deep reaction network analysis that would be infeasible with QM methods.