Our work aims to monitor wheat crop using a variety-based approach by taking into consideration four different phenological stages of wheat crop development. In addition to highlighting the contribution of Red-Edge vegetation indices in mapping wheat dry matter and nitrogen content dynamics, as well as using Random Forest regressor in the estimation of wheat yield, dry matter and nitrogen uptake relying on UAV (Unmanned Aerial Vehicle) multispectral imagery. The study was conducted on an experimental platform with 12 wheat varieties located in Sidi Slimane (Morocco). Several flight missions were conducted using eBee UAV with MultiSpec4C camera according to phenological growth stages of wheat. The proposed methodology is subdivided into two approaches, the first aims to find the most suitable vegetation index for wheat’s biophysical parameters estimation and the second to establish a global model regardless of the varieties to estimate the biophysical parameters of wheat: Dry matter and nitrogen uptake. The two approaches were conducted according to six main steps: (1) UAV flight missions and in-situ data acquisition during four phenological stages of wheat development, (2) Processing of UAV multispectral images which enabled us to elaborate the vegetation indices maps (RTVI, MTVI2, NDVI, NDRE, GNDVI, GNDRE, SR-RE et SR-NIR), (3) Automatic extraction of plots by Object-based image analysis approach and creating a spatial database combining the spectral information and wheat’s biophysical parameters, (4) Monitoring wheat growth by generating dry biomass and wheat’s nitrogen uptake model using exponential, polynomial and linear regression for each variety this step resumes the varietal approach, (5) Engendering a global model employing both linear regression and Random Forest technique, (6) Wheat yield estimation. The proposed method has allowed to predict from 1 up to 21% difference between actual and estimated yield when using both RTVI index and Random Forest technique as well as mapping wheat’s dry biomass and nitrogen uptake along with the nitrogen nutrition index (NNI) and therefore facilitate a careful monitoring of the health and the growth of wheat crop. Nevertheless, some wheat varieties have shown a significant difference in yield between 2.6 and 3.3 t/ha.