Azobenzenes are versatile photoswitches that can be used to generate elaborate optical tools, including photopharmaceuticals. However, the targeted application-guided design of new photoswitches with specific properties remains challenging. We have developed synthetic protocols for derivatives of the dfdc (di-ortho-fluoro-di-ortho-chloro) azobenzene scaffold with chemical alterations in the para-/ortho-positions and performed an in-depth study into the effects of their structures on their photophysical properties with an emphasis on the n → π* absorption band using NMR, UV-vis, and X-ray analysis. The data was used to establish and validate a computational approach that allows to compute realistic UV-vis spectra by combining TD-DFT excited-state calculations from 6000 thermally accessible structures generated through MD simulations while considering the high structural flexibility of ortho-substituted azobenzenes. We added 15 new visible light-operated photoswitches to the toolbox for the development of optical devices with relaxation rates across multiple orders of magnitude and identified several examples with stronger bathochromic shifts than the dfdc azobenzene lead structure. Our combined experimental and computational study forms the foundation for the advanced in silico design and synthesis of new highly red-shifted photoswitches. To showcase the potential of dfdc azobenzenes for the development of chemical tools, we synthesized dfdc-OptoBI-1 and demonstrated its biological activity as a red light-operated activator of TRPC6 channels in HEK293 cells.