Background: Microcephaly is a neurodevelopmental disorder characterized by a head circumference more than two standard deviations below the mean for age and sex. It encompasses a spectrum of genetic (primary) and acquired (secondary) causes, each with distinct pathophysiological mechanisms, imaging findings, hormonal abnormalities, and long-term outcomes. Understanding these differences is essential for accurate diagnosis and early intervention. Objectives: To review and compare the clinical, biochemical, hormonal, imaging, and genetic characteristics of genetic and acquired medical causes of microcephaly in children and identify key prognostic indicators for developmental outcomes. Methods: This review synthesized data from peer-reviewed studies published over the past 25 years. Inclusion criteria encompassed studies involving children with diagnosed microcephaly with available clinical, endocrine, biochemical, and MRI data. A total of 84 original articles and 17 systematic reviews/meta-analyses were evaluated. Parameters were categorized and summarized across 7 comparative tables, focusing on growth patterns, skeletal features, IGF-1 and thyroid hormone profiles, neuroimaging patterns, and genotype-phenotype correlations. Results: Genetic microcephaly often presents with prenatal onset, syndromic features, and proportionate short stature. It was commonly associated with mutations in genes such as ASPM, WDR62, and IGF1R. MRI findings frequently included simplified gyral patterns, cortical migration defects, and cerebellar hypoplasia. Endocrine abnormalities—particularly reduced IGF-1 levels and thyroid dysfunction—were observed in syndromic and non-syndromic forms. Conversely, acquired microcephaly was typically postnatal in onset, secondary to hypoxic-ischemic injury, infections (e.g., Zika virus), or metabolic insults. These cases showed progressive deceleration in head growth and a wider variability in MRI features, including periventricular leukomalacia and white matter loss. Biochemical and hormonal disturbances were less specific but often reflected the underlying systemic condition. Tables 1a–7b highlight these comparative aspects. Conclusions: The review underscores the importance of a multidisciplinary diagnostic approach to microcephaly, integrating clinical evaluation with advanced neuroimaging, hormonal profiling, and genetic testing. Specific MRI patterns can guide the selection of targeted gene panels, while IGF-1 and thyroid hormone levels offer additional diagnostic and prognostic value. Distinguishing between genetic and acquired forms enables more accurate prognostication, facilitates genetic counseling, and informs therapeutic strategies. Future research should emphasize early detection via imaging-genotype algorithms and longitudinal cohort studies to refine outcome prediction and personalize care.