The segmentation of medical images is a crucial and demanding step in medical image processing that offers a solid foundation for subsequent extraction and analysis of medical image data. Although multi-threshold image segmentation is the most used and specialized basic image segmentation technique, it is computationally demanding and often produces subpar segmentation results, hence restricting its application. To solve this issue, this work develops a multi-strategy-driven slime mould algorithm (RWGSMA) for multi-threshold image segmentation. Specifically, the random spare strategy, the double adaptive weigh strategy, and the grade-based search strategy are used to improve the performance of SMA, resulting in an enhanced SMA version. The random spare strategy is mainly used to accelerate the convergence rate of the algorithm. To prevent SMA from falling towards the local optimum, the double adaptive weights are also applied. The grade-based search approach has also been developed to boost convergence performance. This study evaluates the efficacy of RWGSMA from many viewpoints using 30 test suites from IEEE CEC2017 to effectively demonstrate the importance of these techniques in RWGSMA. In addition, numerous typical images were used to show RWGSMA’s segmentation performance. Using the multi-threshold segmentation approach with 2D Kapur’s entropy as the RWGSMA fitness function, the suggested algorithm was then used to segment instances of lupus nephritis. The experimental findings demonstrate that the suggested RWGSMA beats numerous similar rivals, suggesting that it has a great deal of promise for segmenting histopathological images.Copyright © 2023 Elsevier Ltd. All rights reserved.