The current study aimed to predict lymphovascular invasion (LVI) using multiple machine learning algorithms and multi-segmentation positron emission tomography (PET) radiomics in non-small cell lung cancer (NSCLC) patients, offering new avenues for personalized treatment strategies and improving patient outcomes. One hundred and twenty-six patients with NSCLC were enrolled in this study. Various automated and semi-automated PET image segmentation methods were applied, including Local Active Contour (LAC), Fuzzy-C-mean (FCM), K-means (KM), Watershed, Region Growing (RG), and Iterative thresholding (IT) with different percentages of the threshold. One hundred five radiomic features were extracted from each region of interest (ROI). Multiple feature selection methods, including Minimum Redundancy Maximum Relevance (MRMR), Recursive Feature Elimination (RFE), and Boruta, and multiple classifiers, including Multilayer Perceptron (MLP), Logistic Regression (LR), XGBoost (XGB), Naive Bayes (NB), and Random Forest (RF), were employed. Synthetic Minority Oversampling Technique (SMOTE) was also used to determine if it boosts the area under the ROC curve (AUC), accuracy (ACC), sensitivity (SEN), and specificity (SPE). Our results indicated that the combination of SMOTE, IT (with 45% threshold), RFE feature selection and LR classifier showed the best performance (AUC = 0.93, ACC = 0.84, SEN = 0.85, SPE = 0.84) followed by SMOTE, FCM segmentation, MRMR feature selection, and LR classifier (AUC = 0.92, ACC = 0.87, SEN = 1, SPE = 0.84). The highest ACC belonged to the IT segmentation (with 45 and 50% thresholds) alongside Boruta feature selection and the NB classifier without SMOTE (ACC = 0.9, AUC = 0.78 and 0.76, SEN = 0.7, and SPE = 0.94, respectively). Our results indicate that selection of appropriate segmentation method and machine learning algorithm may be helpful in successful prediction of LVI in patients with NSCLC with high accuracy using PET radiomics analysis.