In the past few years, the quest for visible light active TiO2-based photocatalysts has been a hotly debated research topic in both scientific and practical fields. Attempting to meet the same purpose, in this study, a visible-driven nanocomposite, l-Histidine (2 wt%)-TiO2-CdS (7:1) nanocomposite, was dip-coated on the glass disc (rough vs. smooth) after the optimum composition was identified by varying the l-Histidine and CdS quantities. The prepared nanoparticles and coated catalyst on the disc were characterized by XRD, FT-IR, X-ray (FE-SEM/EDX), DRS, PL analyses in terms of their structural and optical properties as well as morphology. The coated photocatalyst was tested for photocatalytic degradation of direct red 16 (DR16) as an azo dye. The photodegradation process variables, including disc rotation speed, light intensity, irradiation time, and type of disc (smooth vs. rough glass disc)) were also modeled and optimized by central composite design (CCD). At the optimum conditions obtained, the effects of reaction time, pH, DR16 concentration, and aeration were investigated. After 3 h of using the rough disc (disc II) at a disc rotation speed of 100 rpm as well as a light intensity of 13 lumens per m2, DR16 was completely degraded. The pH and DR16 concentration seemed to have the reverse impact on the photodegradation process, whereas aeration had such a positive effect. By analyzing the effects of various scavengers, the contribution of reactive species in the photodegradation process was thoroughly investigated. Furthermore, the reusability results indicate no significant change in the photodegradation efficiency after four cycles.