Photoresist grids (PGs) hosting uniform ligand-doped liquid crystal (LC) films with large active regions of 1 × 1 cm2 are fabricated in this work. The length and thickness of the meshes of the PGs are optimized by studying the anchoring energy of the alignment layers of the LC films. The PGs hosting the LC films exhibit the significant transition of optical signals from dark to bright after the binding of ligand and Hg2+ reorients the LC. The optimized PGs hosting the LC films have an extremely low limit of detection (LOD) of 5.0 ± 0.4 femtomolar (fM) for detecting Hg2+ in aqueous solutions. The LOD is 2 × 106 times lower than those of current LC sensors, and 24 times lower than those of current electrochemical sensors. Without using a polarized optical microscope, the image of a PG hosting an LC film is clearly observed by naked eyes when the film is exposed to an aqueous solution with 5.0 ± 0.4 fM Hg2+. The extremely low LOD and real naked-eye detection are great achievements for the practical applications of LC sensors.