A novel nanoparticle mediated methodology for laser photocoagulation of the inner retina to achieve tissue selective treatment is presented. Methods Transport of 527 nm, 577 nm, and 810 nm laser, heat deposition and eventual thermal damage in vitreous, retina, RPE, choroid and sclera were modelled using Bouguer-Beer-Lambert law of absorption and solved numerically using the finite volume method. Nanoparticles were designed using Mie theory of scattering. Performance of the new photocoagulation strategy using gold nanospheres and gold-silica nanoshells was compared to that of conventional methods without nanoparticles. For experimental validation, vitreous cavity of ex vivo porcine eyes was infused with gold nanospheres. After ~6 hours of nanoparticle diffusion, the porcine retina was irradiated with a green laser and imaged simultaneously using a spectral domain optical coherence tomography (Spectralis SD-OCT, Heidelberg Engineering). Results Our computational model predicted a significant spatial shift in the peak temperature from RPE to the inner retinal region when infused with nanoparticles. Arrhenius thermal damage in the mid-retinal location was achieved in ~14 ms for 527 nm laser thereby reducing the irradiation duration by ~30 ms compared to treatment without nanoparticles. In ex vivo porcine eyes infused with gold nanospheres, SD-OCT retinal images revealed a lower thermal damage and expansion at RPE due to laser photocoagulation. Conclusion Nanoparticle infused laser photocoagulation strategy provided a selective inner retinal thermal damage with significant decrease in laser power and laser exposure time. Significance The proposed treatment strategy shows possibilities for an efficient and highly selective inner retinal laser treatment.