Accurate estimation of duration of surgery (DOS) can lead to cost-effective utilization of surgical staff and operating rooms and decrease patients’ waiting time. In this study, we present a supervised DOS nonlinear regression prediction model whose accuracy outperforms earlier results. In addition, unlike previous studies, we identify the features that influence DOS prediction. Further, in difference from others, we study the causal relationship between the feature set and DOS. The feature sets used in prior studies included a subset of the features presented in this study. This study aimed to derive influential effectors of duration of surgery via optimized prediction and causality analysis. We implemented an array of machine learning algorithms and trained them on datasets comprising surgery-related data, to derive DOS prediction models. The datasets we acquired contain patient, surgical staff, and surgery features. The datasets comprised 23,293 surgery records of eight surgery types performed over a 10-year period in a public hospital. We have introduced new, unstudied features and combined them with features adopted from previous studies to generate a comprehensive feature set. We utilized feature importance methods to identify the influential features, and causal inference methods to identify the causal features. Our model demonstrates superior performance in comparison to DOS prediction models in the art. The performance of our DOS model in terms of the mean absolute error (MAE) was 14.9 minutes. The algorithm that derived the model with the best performance was the gradient boosted trees (GBT). We identified the 10 most influential features and the 10 most causal features. In addition, we showed that 40% of the influential features have a significant (p-value = 0.05) causal relationship with DOS. We developed a DOS prediction model whose accuracy is higher than that of prior models. This improvement is achieved via the introduction of a novel feature set on which the model was trained. Utilizing our prediction model, hospitals can improve the efficiency of surgery schedules, and by exploiting the identified causal relationship, can influence the DOS. Further, the feature importance methods we used can help explain the model’s predictions.