Abstract Background Malaria is a serious public health concern worldwide. Early and accurate diagnosis is essential for controlling the disease’s spread and avoiding severe health complications. Manual examination of blood smear samples by skilled technicians is a time-consuming aspect of the conventional malaria diagnosis toolbox. Malaria persists in many parts of the world, emphasising the urgent need for sophisticated and automated diagnostic instruments to expedite the identification of infected cells, thereby facilitating timely treatment and reducing the risk of disease transmission. This study aims to introduce a more lightweight and quicker model—but with improved accuracy—for diagnosing malaria using a YOLOv4 (You Only Look Once v. 4) deep learning object detector. Methods The YOLOv4 model is modified using direct layer pruning and backbone replacement. The primary objective of layer pruning is the removal and individual analysis of residual blocks within the C3, C4 and C5 (C3–C5) Res-block bodies of the backbone architecture’s C3-C5 Res-block bodies. The CSP-DarkNet53 backbone is simultaneously replaced for enhanced feature extraction with a shallower ResNet50 network. The performance metrics of the models are compared and analysed. Results The modified models outperform the original YOLOv4 model. The YOLOv4-RC3_4 model with residual blocks pruned from the C3 and C4 Res-block body achieves the highest mean accuracy precision (mAP) of 90.70%. This mAP is > 9% higher than that of the original model, saving approximately 22% of the billion floating point operations (B-FLOPS) and 23 MB in size. The findings indicate that the YOLOv4-RC3_4 model also performs better, with an increase of 9.27% in detecting the infected cells upon pruning the redundant layers from the C3 Res-block bodies of the CSP-DarkeNet53 backbone. Conclusions The results of this study highlight the use of the YOLOv4 model for detecting infected red blood cells. Pruning the residual blocks from the Res-block bodies helps to determine which Res-block bodies contribute the most and least, respectively, to the model’s performance. Our method has the potential to revolutionise malaria diagnosis and pave the way for novel deep learning-based bioinformatics solutions. Developing an effective and automated process for diagnosing malaria will considerably contribute to global efforts to combat this debilitating disease. We have shown that removing undesirable residual blocks can reduce the size of the model and its computational complexity without compromising its precision. Graphical Abstract