Abstract Deep neural networks (DNNs) have shown success in image classification, with high accuracy in recognition of everyday objects. Performance of DNNs has traditionally been measured assuming human accuracy is perfect. In specific problem domains, however, human accuracy is less than perfect and a comparison between humans and machine learning (ML) models can be performed. In recognising everyday objects, humans have the advantage of a lifetime of experience, whereas DNN models are trained only with a limited image dataset. We have tried to compare performance of human learners and two DNN models on an image dataset which is novel to both, i.e. histological images. We thus aim to eliminate the advantage of prior experience that humans have over DNN models in image classification. Ten classes of tissues were randomly selected from the undergraduate first year histology curriculum of a Medical School in North India. Two machine learning (ML) models were developed based on the VGG16 (VML) and Inception V2 (IML) DNNs, using transfer learning, to produce a 10-class classifier. One thousand (1000) images belonging to the ten classes (i.e. 100 images from each class) were split into training (700) and validation (300) sets. After training, the VML and IML model achieved 85.67 and 89% accuracy on the validation set, respectively. The training set was also circulated to medical students (MS) of the college for a week. An online quiz, consisting of a random selection of 100 images from the validation set, was conducted on students (after obtaining informed consent) who volunteered for the study. 66 students participated in the quiz, providing 6557 responses. In addition, we prepared a set of 10 images which belonged to different classes of tissue, not present in training set (i.e. out of training scope or OTS images). A second quiz was conducted on medical students with OTS images, and the ML models were also run on these OTS images. The overall accuracy of MS in the first quiz was 55.14%. The two ML models were also run on the first quiz questionnaire, producing accuracy between 91 and 93%. The ML models scored more than 80% of medical students. Analysis of confusion matrices of both ML models and all medical students showed dissimilar error profiles. However, when comparing the subset of students who achieved similar accuracy as the ML models, the error profile was also similar. Recognition of ‘stomach’ proved difficult for both humans and ML models. In 04 images in the first quiz set, both VML model and medical students produced highly equivocal responses. Within these images, a pattern of bias was uncovered–the tendency of medical students to misclassify ‘liver’ tissue. The ‘stomach’ class proved most difficult for both MS and VML, producing 34.84% of all errors of MS, and 41.17% of all errors of VML model; however, the IML model committed most errors in recognising the ‘skin’ class (27.5% of all errors). Analysis of the convolution layers of the DNN outlined features in the original image which might have led to misclassification by the VML model. In OTS images, however, the medical students produced better overall score than both ML models, i.e. they successfully recognised patterns of similarity between tissues and could generalise their training to a novel dataset. Our findings suggest that within the scope of training, ML models perform better than 80% medical students with a distinct error profile. However, students who have reached accuracy close to the ML models, tend to replicate the error profile as that of the ML models. This suggests a degree of similarity between how machines and humans extract features from an image. If asked to recognise images outside the scope of training, humans perform better at recognising patterns and likeness between tissues. This suggests that ‘training’ is not the same as ‘learning’, and humans can extend their pattern-based learning to different domains outside of the training set.