Background: Antibiotic exposure in the pediatric intensive care unit (PICU) is very high, although 50% of all antibiotics may be unnecessary. We aimed to determine the utility of simple bedside screening tools and predicting factors to avoid antibiotic overuse in the ICU among children with diarrhea and critical illness. Methods: We conducted a retrospective, single-center, case-control study that included children aged 2–59 months who were admitted to PICU with diarrhea and critical illness between 2017 and 2020. Results: We compared young children who did not receive antibiotics (cases, n = 164) during ICU stay to those treated with antibiotics (controls, n = 346). For predicting the ‘no antibiotic approach’, the sensitivity of a negative quick Sequential Organ Failure Assessment (qSOFA) was similar to quick Pediatric Logistic Organ Dysfunction-2 (qPELOD-2) and higher than Systemic Inflammatory Response Syndrome (SIRS). A negative qSOFA or qPELOD-2 score calculated during PICU admission is superior to SIRS to avoid antibiotic overuse in under-five children. The logistic regression analysis revealed that cases were more often older and independently associated with hypernatremia. Cases less often had severe underweight, altered mentation, age-specific fast breathing, lower chest wall in-drawing, adventitious sound on lung auscultation, abdominal distension, developmental delay, hyponatremia, hypocalcemia, and microscopic evidence of invasive diarrhea (for all, p < 0.05). Conclusion: Antibiotic overuse could be evaded in PICU using simple bedside screening tools and clinical characteristics, particularly in poor resource settings among children with diarrhea.