Background: Fever of Unknown Origin (FUO) is a diagnostic challenge in pediatrics, often stemming from zoonotic infections. In southern Israel, brucellosis and rickettsiosis are endemic and share overlapping clinical features, making diagnosis difficult. We compared the demographic, clinical, and laboratory characteristics of pediatric brucellosis and rickettsiosis to aid in distinguishing between these diseases and guide early empirical treatment. Methods: We performed a retrospective cohort study, conducted between 2005 and 2020, on children who tested positive for either rickettsia or brucella. Data on demographic, clinical, laboratory, treatment, and outcome parameters were analyzed using descriptive, univariate, and multivariate statistical methods. Results: Overall, 775 patients were included, 440 with brucellosis and 335 with rickettsiosis. The majority of patients were of Bedouin ethnicity (99.5% and 90.7%, respectively). In univariate analysis, brucellosis was associated with male gender, young age, limping, anemia, and prolonged hospitalization duration. Rickettsiosis was characterized by high-grade fever, rash, headache, thrombocytopenia, elevated C-reactive protein (CRP), and gastrointestinal, respiratory, and neurological symptoms. Mortality rates were low in both groups (≤0.5%). In multivariate analysis, brucellosis was associated with limping (odds ratio = 7.27; with 95% confidence interval of 5.15–10.38), hemoglobin <10 mg/dL (2.01; 1.14–3.64), age <5 years (1.95; 1.25–3.07), warm season (1.84; 1.31–2.59), and male gender (1.57; 1.10–2.25). Rickettsiosis was associated with a rash (9.06; 3.91–24.9), CRP ≥5 mg/dL (4.03; 1.86–9.81), headache (3.01; 1.75–5.30), thrombocytopenia (2.61; 1.23–6.06), leukopenia (1.88; 1.19–2.98), and temperature ≥39.0 °C (1.66; 1.03–2.68). Conclusions: Brucellosis and rickettsiosis differ demographically and clinically in FUO cases. These findings highlight the importance of distinguishing between the two diseases for early diagnosis and targeted management, ultimately improving patient outcomes.