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Crop yield prediction is of great practical significance for farmers to make reasonable decisions, such as decisions on crop insurance, storage demand, cash flow budget, fertilizer, water and other input factors. The traditional yield measurement method is sampling surveys, which require a large area of destructive sampling of cotton fields and consume considerable time and labor costs. This study established a cotton yield estimation model based on time series Unmanned Aerial Vehicle (UAV) remote sensing data. The U-Net semantic segmentation network is used to recognize and extract the boll opening pixels in high-resolution visible images, and the boll opening pixel percentage (BOP) is calculated according to the network extraction results. By combining the multispectral images and the pixel coverage of cotton bolls, a Bayesian regularization BP (back propagation) neural network was used to predict cotton yields. In order to simplify the input parameters of the model, the stepwise sensitivity analysis method is used to eliminate redundant variables and obtain the optimal input feature set. The experimental results show that the R2 of the proposed model is 0.853 at the scale of 0.81 m2 (average results of ten-fold cross validation). This study provides a method that can simultaneously meet the requirements of large-area and small-scale forecasting of cotton yields and provides a new idea for cotton yield measurement and breeding screening.