Numerous industrial applications of machine learning feature critical issues that need to be addressed. This work proposes a framework to deal with these issues, such as competing objectives and class imbalance in designing a machine vision system for the in-line detection of surface defects on glass substrates of thin-film transistor liquid crystal displays (TFT-LCDs). The developed inspection system composes of (i) feature engineering: extraction of only the defect-relevant features from images using two-dimensional wavelet decomposition and (ii) training ensemble classifiers (proof of concept with a C5.0 ensemble, random forests (RF), and adaptive boosting (AdaBoost)). The focus is on cost sensitivity, increased generalization, and robustness to handle class imbalance and address multiple competing manufacturing objectives. Comprehensive performance evaluation was conducted in terms of accuracy, sensitivity, specificity, and the Matthews correlation coefficient (MCC) by calculating their 12,000 bootstrapped estimates. Results revealed significant differences (p < 0.05) between the three developed diagnostic algorithms. RFR (accuracy of 83.37%, sensitivity of 60.62%, specificity of 89.72%, and MCC of 0.51) outperformed both AdaBoost (accuracy of 81.14%, sensitivity of 69.23%, specificity of 84.48%, and MCC of 0.50) and the C5.0 ensemble (accuracy of 78.35%, sensitivity of 65.35%, specificity of 82.03%, and MCC of 0.44) in all the metrics except sensitivity. AdaBoost exhibited stronger performance in detecting defective TFT-LCD glass substrates. These promising results demonstrated that the proposed ensemble approach is a viable alternative to manual inspections when applied to an industrial case study with issues such as competing objectives and class imbalance.