In this work, the performance of a pilot-scale solar CPC reactor was evaluated for the degradation of commercial acetaminophen, using TiO2 P25 as a catalyst. The statistical Taguchi’s method was used to estimate the combination of initial pH and catalyst load while tackling the variability of the solar radiation intensity under tropical weather conditions through the estimation of the signal-to-noise ratios (S/N) of the controllable variables. Moreover, a kinetic law that included the explicit dependence on the local volumetric rate of photon absorption (LVRPA) was used. The radiant field was estimated by joining the Six Flux Model (SFM) with a solar emission model based on clarity index (KC), whereas the mass balance was coupled to the hydrodynamic equations, corresponding to the turbulent regime. For scaling-up purposes, the ratio of the total area-to-total-pollutant volume (AT/VT) was varied for observing the effect of this parameter on the overall plant performance. The Taguchi’s experimental design results showed that the best combination of initial pH and catalyst load was 9 and 0.6 g L−1, respectively. Also, full-scale plants would require far fewer ratios of AT/VT than for pilot or intermediate-scale ones. This information may be beneficial for reducing assembling costs of photocatalytic reactors scaling-up.