Background/Objectives: Infants exposed to opioids in utero are at risk of neonatal opioid withdrawal syndrome (NOWS). We compared clinical, family-related, and classification-derived resource outcomes before and after implementation of Eat, Sleep, Console (ESC) in an Appalachian hospital. Methods: This single-center retrospective cohort study compared outcomes of opioid-exposed neonates assessed with Finnegan Scoring system (FNASS) (Epoch 1, N = 252) versus the Eat, Sleep, Console (ESC) method (Epoch 2, N = 100). Multivariable logistic regression and gamma generalized linear models with log links evaluated outcomes after adjustment for gestational age and maternal tobacco, fentanyl, and methamphetamine exposure. Results: ESC was associated with lower adjusted odds of NOWS classification (adjusted odds ratio (aOR) 0.32, 95% Confidence Interval (CI) 0.19–0.54), rescue morphine (aOR 0.36, 95% CI 0.17–0.75), and morphine taper (aOR 0.32, 95% CI 0.12–0.85). Adjusted mean length of stay was lower (ratio 0.66, 95% CI 0.54–0.79). Adjusted associations with foster care discharge (aOR 0.97, 95% CI 0.49–1.93) and parental involvement (aOR 1.24, 95% CI 0.66–2.32) were not statistically significant. Conclusions: ESC implementation was associated with shorter hospitalization and less pharmacological treatment after adjustment for measured differences between epochs. Unadjusted differences in foster care discharge and parental involvement did not persist after adjustment. The observational, sequential-epoch design precludes causal attribution.