Signal transduction carried out by chemical messengers and various kinases plays an essential role in regulating all biological processes. Visualizing the spatial compartmentation of these signaling events using genetically encodable biosensors can provide invaluable insights into how individual signaling agents are able to execute multiple cell functions with high specificity. However, current biosensors are limited in both multiplexing capability and tissue imaging compatibility. In this study, we engineered an array of far-red chemigenetic biosensors to probe protein kinase A (PKA) signaling by using a HaloTag7 self-labeling protein tag as the reporting unit. We find that these chemigenetic PKA sensors achieve up to 1250% dynamic range, drastically outperforming any other far-red PKA sensors currently available. We then show that this far-red chemigenetic design is generalizable to visualize the activity of other signaling molecules with high sensitivity. We also demonstrate that these far-red chemigenetic sensors are able to provide spatiotemporal information of PKA signaling via 4D imaging of PKA activity in HEK293T spheroids and murine pancreatic beta cell islets. Thus, the engineered chemigenetic sensors enable highly sensitive imaging of cell signaling activity in a previously unoccupied far-red optical window.