Nanoscale devices that can respond to external stimuli have potential applications in drug delivery, biosensing, and molecular computation. Construction using DNA has provided many such devices that can respond to cues such as nucleic acids, proteins, pH, light, or temperature. However, simultaneous control of molecular devices is still limited. Here, we present orthogonal control of DNA nanoswitches using physical (light) and biochemical (enzyme and nucleic acid) triggers. Each one of these triggers controls the reconfiguration of specific nanoswitches from locked to open states within a mixture and can be used in parallel to control a combination of nanoswitches. Such dynamic control over nanoscale devices allows the incorporation of tunable portions within larger structures as well as spatiotemporal control of DNA nanostructures.