Various embodiments of the present disclosure disclose methods and systems for heat exchange in an opto-fluidic instrument. The opto-fluidic instrument includes a sample interface module (SIM), an illumination module, a camera module, and a reagent deck. A coolant from a coolant reservoir is directed into one or more of the modules so that heat exchange occurs at each module with the coolant. The heated coolant from the one or more modules flows to a radiator for cooling, for example, with fans flowing ambient air over the radiator, before the cooled coolant is returned to the coolant reservoir for subsequent use in cooling the modules.