Objectives: Diuretics are frequently used in bronchopulmonary dysplasia (BPD), yet evidence describing their short-term physiological effects remains limited. This study aimed to describe early changes in respiratory support parameters and safety outcomes following combined oral spironolactone and hydrochlorothiazide (SP/HCTZ) therapy in preterm infants with BPD. Methods: A retrospective, single-center before–after observational study was conducted. Preterm infants diagnosed with BPD who initiated SP/HCTZ therapy were included. Respiratory parameters (FiO2, PEEP, and flow rate) and serum electrolytes were compared between Day 1 (initiation) and Day 3 of treatment. A predefined clinical response was defined as either a ≥10% reduction in FiO2 or a step-down in respiratory support modality. Results: Fifty-six infants (mean gestational age 27.7 ± 2.3 weeks) were analyzed. After 72 h of SP/HCTZ therapy, mean FiO2 decreased from 26.2 ± 6.3% to 22.4 ± 3.4% (p < 0.001). Significant reductions were also observed in PEEP and cannula flow rates (p = 0.004 and p = 0.003, respectively). Overall, 39 infants (69.6%) met the predefined clinical response criteria. The prevalence of hyponatremia (Na < 133 mmol/L) increased from 7.1% at baseline to 25.0% on Day 3 (p = 0.039). Conclusions: Initiation of SP/HCTZ was temporally associated with short-term reductions in respiratory support parameters; however, these findings should be interpreted as associations rather than treatment effects. Given the increased frequency of hyponatremia by Day 3, close electrolyte monitoring appears warranted during the early phase of therapy.