Remote sensing (RS) provides operational monitoring of terrestrial vegetation. For optical RS, vegetation information is generally derived from surface reflectance (ρ). More generally, vegetation indices (VIs) are built on the basis of ρ as proxies for vegetation traits. At canopy level, ρ can be affected by a variety of factors, including leaf constituents, canopy structure, background reflectivity, and sun-sensor geometry. Consequently, VIs are mixtures of different information. In this study, a global sensitivity analysis (GSA) is made for several commonly used satellite-derived VIs in order to better understand the application of these VIs at large scales. The sensitivities of VIs to different parameters are analyzed on the basis of PROSPECT-SAIL (PROSAIL) radiative transfer model simulations, which apply for homogeneous canopies, and random forest (RF) learning. Specifically, combined factors such as canopy chlorophyll content (CCC) and canopy water content (CWC) are introduced in the RF-based GSA. We find that for most VIs, the leaf area index is the most influential factor, while the broad-band sensor-derived enhanced VI (EVI) exhibits a strong sensitivity to CCC, and the universal normalized VI (UNVI) is sensitive to CWC. The potential and uncertainty for the application of all the considered VIs are analyzed according to the GSA results. The results can help to improve the use of VIs in different contexts, and the RF-based GSA method can be further applied in more sophisticated situations.