Social emotional learning (SEL) programs are increasingly being implemented in elementary schools to facilitate development of social competencies, decision-making skills, empathy, and emotion regulation and, in effect, prevent poor outcomes such as school failure, conduct problems, and eventual substance abuse. SEL programs are designed to foster these abilities in children with a wide range of behavioral, social, and learning needs in the classroom, including children who are economically disadvantaged. In a previous study of kindergartners residing in a high-poverty community (
N
= 327 at baseline), we observed significant behavioral improvements in children receiving an SEL program—The PATHS
®
curriculum (PATHS)—relative to an active control condition within one school year. The present investigation sought to determine whether these improvements were sustained over the course of two school years with intervention and an additional year when intervention was no longer provided. Further, using multilevel models, we examined whether baseline measures of neurocognition and stress physiology—known to be adversely impacted by poverty—moderated heterogeneous outcomes. Finally, a preliminary linear regression analysis explored whether neurocognition and physiological stress reactivity (heart rate variability, HRV) predict change in outcomes postintervention. Results confirmed that students who received PATHS sustained significant behavioral improvements over time. These effects occurred for the full sample, irrespective of putative baseline moderators, suggesting that children in high-risk environments may benefit from SEL interventions irrespective of baseline cognitive functioning as a function of overall substantial need. Of interest is that our exploratory analysis of change from waves three to four after the intervention concluded brought to light possible moderation by baseline physiology. Should subsequent studies confirm this finding, one plausible explanation may be that, when an intervention providing protective effects is withdrawn, children with higher HRV may not be able to regulate physiological stress responses to environmental challenges, leading to an uptick in maladaptive behaviors. In reverse, children with lower HRV—generally associated with poorer emotion regulation—may incur relatively greater gains in behavioral improvement due to lesser sensitivity to the environment, enabling them to continue to accrue benefits. Results are discussed in the context of possible pathways that may be relevant to understanding the special needs of children reared in very low-income, high-stress neighborhoods.