Estimating leaf chlorophyll contents through leaf reflectance spectra is efficient and nondestructive, but the actual dataset always based on a single or a few kinds of specific species, has a limitation and instability for a common use. To address this problem, a combination of multiple spectral indices and a model simulated dataset are proposed in this paper. Six spectral indices are selected, including Blue Green Index (BGI), Photochemical Reflectance Index (PRI_5), Triangle Vegetation Index (TVI), Chlorophyll Absorption Ratio Index (CARI), Carotenoid Reflectance Index (CRI) and the green peak reflectance (R525). Both stepwise linear regression (SLR) and back-propagation artificial neural network (ANN) are used to combine the six spectral indices for the estimation of chlorophyll content (Cab). In addition, to overcome the limitation of actual dataset, a “big data” is applied by a within-leaf radiation transfer model (PROSPECT) to generate a large number of simulated samples with varying biochemical and biophysical parameters. 30% of the simulated dataset (SIM30) and an experimental dataset are used for validation. Compared with linear regression method, NN yields better result with R2 = 0.96 and RMSE = 5.80ug.cm−2 for Cab if validated by SIM30, while R2 = 0.95 and RMSE = 6.39ug.cm−2 for SLR. NN also gives satisfactory result with R2 = 0.80 and RMSE = 5.93ug.cm−2 for Cab if validated by LOPEX dataset, however, the SLR only gets 0.72 of R2 and 12.20ug.cm−2 of RMSE. The results indicate that integrating multiple spectral indices can improve the Cab estimating accuracy with a better stability in different kind of species and the model simulated dataset can make up the shortfall of actual measured dataset.