Textiles are important components for the development of lightweight and flexible displays useful in smart materials. In particular, halochromic textiles are fibrous materials with a color-changing ability triggered by pH variations mainly based on pH-sensitive dye molecules. Recently, a novel class of 2-aminoimidazole azo dyes was developed with distinct substituent patterns. In this work, silk fabric was functionalized through exhaustion for the first time with one of these dyes (AzoIz.Pip). The halochromic properties of the dye were assessed in an aqueous solution and after silk functionalization. The solutions and the fabrics were thoroughly analyzed by ultraviolet-visible (UV-vis) spectra, color strength (K/S), color difference (∆E), CIE L*a*b* coordinates, and the ultraviolet protection factor (UPF). The dyeing process was optimized, and the halochromic performance (and reversibility) was assessed in universal Britton–Robinson buffers (ranging from pH 3 to 12) and artificial body fluids (acid and alkaline perspiration, and wound exudate). AzoIz.Pip showed vibrant colors and attractive halochromic properties with a hypsochromic shift from blue (557 nm) to magenta (536 nm) in aqueous buffered solutions. Similarly, the functionalized silk showed a shift in wavelength of the maximum K/S value from 590 nm to 560 nm when pH increases. The silk fabric showed a high affinity to AzoIz.Pip, and promoted additional color stabilization of the dye, avoiding color loss as observed when the dye is in solution at alkaline pH after 24 h. The color reversibility was effective up to the fourth cycle and the fastness tests denoted suitable results, except washing fastness. The cytotoxicity of the silk fabric extracts was assessed, depicting reduced viability of HaCaT cells to <70% only when the dye concentration in the fabric is higher or equal to 64 μg·mL−1. Nevertheless, lower concentrations were also very effective for the halochromic performance in silk. These materials can thus be a helpful tool for developing sensors in several sectors such as biomedicine, packaging, filtration, agriculture, protective apparel, sports, camouflage, architecture, and design.