Biofouling of ships’ internal seawater systems (ISS) can cause significant operational issues and is a potential transfer mechanism for marine nonindigenous species. This study used an engine room simulator and economic evaluation to quantify impacts on commercial ship performance of biofouling occlusion within various ISS nodes (sea chest, strainer, and heat exchangers). A characteristic hockey-stick relationship between occlusion and impact emerged, whereby engine room systems could tolerate up to 55% occlusion of a single node without operational impact, followed by rapid performance deterioration. The relative magnitude of impacts varied by ISS node and in response to changes in ambient seawater temperatures. System tolerance was much lower when simultaneous occlusion of multiple nodes was assessed. In economic terms, consequences included required freight rate increases of 1–26% prior to forced (automatic) slowdown of the ship and up to 82% increases if slowdown conditions were required.