Background Breast cancer is a progressive disease, with conditions secondary to primary breast cancer being among the more common causes of malignancy-related deaths in women. Early diagnosis can halt disease progression and significantly improve patient's survival. Microcalcifications detected on mammograms may be an indicator of breast cancer. This study assessed the diagnostic accuracy of microcalcifications seen on mammograms for the detection of malignant breast disease when compared with histopathology. Materials and methods This study enrolled 144 women referred to the Radiology Department of Aga Khan University Hospital in Karachi, Pakistan, for mammograms and who were found to have suspicious microcalcifications, for which they underwent subsequent biopsy with histopathology over one year. The accuracy of microcalcifications, along with their sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV), were assessed relative to histopathology results. Results Compared with histopathology results, microcalcifications had a sensitivity of 88%, and specificity of 62.8%, a PPV of 55.7%, and an NPV of 90.8%. The overall accuracy of microcalcifications was 71.5%. Conclusions The presence of microcalcifications on mammograms may predict breast malignancy. Studies with larger numbers of patients are required to determine whether microcalcifications have higher specificity and PPV relative to breast histopathology.