Ibuprofen is one of the best-known nonsteroidal anti-inflammatory and analgesic drugs. Following the previous work, the current study is focused on estimating the effect of different chromatographic conditions on the sensitivity of thin-layer chromatography in combination with UV densitometry, i.e., the detection and quantification of ibuprofen in a wide range of its concentrations including the lowest limits of detection (LOD) and quantification (LOQ). For this purpose, a reliable and easy-to-use calculation procedure for LOD and LOQ determination is presented in this work. In addition, the impact of type plates and mobile phase composition on the LOD and LOQ, respectively, of this active substance is accurately described. The results of detection and the quantification level of ibuprofen obtained under applied chromatographic conditions confirmed the utility of silica gel plates as well as silica gel bonded phases (i.e., reversed-phase (RP) plates) in the thin-layer chromatography (TLC)-densitometric analysis of ibuprofen at a low level, i.e., from several nanograms (below one microgram) to a few micrograms/spot. Among all chromatographic systems tested, the best are those consisting of silica gel 60F254 plates with concentrating zone (1.05583) and the mixture of n-hexane:ethyl acetate:glacial acetic acid in ratio 36:12:2 (v/v/v) as well as RP plates, i.e., RP-18F254 aluminum plates developed with methanol:water in volume composition 40:10 (v/v). These chromatographic systems allowed quantifying ibuprofen in the amount of 0.229 µg/spot and 0.228 µg/spot, which is less than 1 µg/spot. It can be stated that different chromatographic systems in combination with UV densitometric scanning at 224 nm proposed in this work can be successfully applied for the cost-effective and sensitive determination of ibuprofen as a widely used drug component as well as a residual in domestic wastewater. It was found that the modification of silica gel as well as the layer thickness of unmodified or modified silica gel 60 can influence the quality of chromatograms and the detection/quantification of ibuprofen in both normal phase (NP) and RP systems. Therefore, to obtain the best possible LOD and LOQ values of ibuprofen with precoated layers, suitable mobile phase and chromatographic plates are required.