The investigation of lie detection methods based on P300 potentials has drawn much interest in recent years. We presented a novel algorithm to enhance signal-to-noise ratio (SNR) of P300 and applied it in lie detection to increase the classification accuracy. Thirty-four subjects were divided randomly into guilty and innocent groups, and the EEG signals on 14 electrodes were recorded. A novel spatial denoising algorithm (SDA) was proposed to reconstruct the P300 with a high SNR based on independent component analysis. The differences between the proposed method and our/other early published methods mainly lie in the extraction and feature selection method of P300. Three groups of features were extracted from the denoised waves; then, the optimal features were selected by the F-score method. Selected feature samples were finally fed into three classical classifiers to make a performance comparison. The optimal parameter values in the SDA and the classifiers were tuned using a grid-searching training procedure with cross-validation. The support vector machine (SVM) approach was adopted to combine with an F-score because this approach had the best performance. The presented model F-score_SVM reaches a significantly higher classification accuracy for P300 (specificity of 96.05%) and non-P300 (sensitivity of 96.11%) compared with the results obtained without using SDA and compared with the results obtained by other classification models. Moreover, a higher individual diagnosis rate can be obtained compared with previous methods, and the presented method requires only a small number of stimuli in the real testing application.