Abstract Internal climate variability (ICV) often violates the assumptions of statistical methods, and the climate research community does not have an established approach for addressing resulting biases. Here we argue for a technique we call climate model Large-Ensemble Monte-Carlo (LENS-MC) to inform the selection of statistical methods for real-world application. Until now, scientists have often made best efforts to select methods based on assumptions about the mathematical properties of ICV. LENS-MC relaxes these assumptions and justifies method selection, potentially for a wide range of statistical analyses. We demonstrate LENS-MC using a case study of statistical errors in 20-year trends in global temperature and top-of-atmosphere (TOA) flux series, comparing results with standard ordinary least squares (OLS). OLS commonly underestimates trend uncertainties, resulting in a higher likelihood of falsely reporting statistically significant trends or changes in trends, for example reporting p<0.05 in 20-year temperature trends when the statistics are actually equivalent to p<0.56. LENS-MC tests result in the selection of methods that almost eliminate the low bias in OLS trend standard errors. Using the suggested methods, researchers are less likely to mistakenly report significant trends, and LENS-MC could be widely applied to statistical climate analysis for which model output is available, provided that model ICV displays similar statistical structure, such as in autocorrelation, to observed ICV.