Therapeutic preparations of insulin often contain phenolic molecules, which can impact both pharmacokinetics and shelf life. Thus, understanding the interactions of insulin and phenolic molecules can aid in designing improved therapeutics. In this study, we use molecular dynamics to investigate phenol release from the insulin hexamer. Leveraging recent advances in methods for analyzing molecular dynamics data, we expand on existing simulation studies to identify and quantitatively characterize six phenol binding/unbinding pathways for wild-type and A10 Ile → Val and B13 Glu → Gln mutant insulins. A number of these pathways involve large-scale opening of the primary escape channel, suggesting that the hexamer is much more dynamic than previously appreciated. We show that phenol unbinding is a multipathway process, with no single pathway representing more than 50% of the reactive current and all pathways representing at least 10%. We use the mutant simulations to show how the contributions of specific pathways can be rationally manipulated. Predicting the net effects of mutations is more challenging because the kinetics depend on all of the pathways, demanding quantitatively accurate simulations and experiments.