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Many children in low- and middle-income countries face adversities that put them at risk of not reaching their developmental potential. We investigated risk and protective factors influencing cognitive, language, and motor development at 5 years of age in a South African birth cohort and assessed which early-life factors shaped developmental trajectories between 2-5 years.Methods In the Drakenstein Child Health Study, 728 mother–child dyads were followed from the antenatal period through 5-years. Neurodevelopmental domain outcomes were measured at 5-years using standardized instruments. Random forest models identified key predictors of each domain, these were then examined in multivariable linear regressions. Longitudinal trajectories from 2-5 years were explored with latent class growth analysis; random forest and post-hoc logistic models examined determinants of class membership.Results Higher maternal education was the strongest socioeconomic factor associated with better cognitive scores (β = +5.0, p<0.001; 95%CI: 2.74,7.27) and language outcomes (β = +2.92, p<0.001; 95%CI: 1.49,4.34) with increased birthweight the strongest physical factor associated with higher cognitive scores (β=+2.34, p<0.026; 95%CI: 0.28,4.40) at 5 years. Maternal psychosocial stressors, including depression (β=-0.46; p=0.002; 95%CI:-0.75,-0.17) and physical health, including HIV-exposure (β=–0.51, p<0.001; 95%CI:-0.80,-0.23), were associated with lower expressive language scores. Trajectory analysis revealed 8.8–16% of children demonstrated developmental catch-up between 2-5 years, with female sex and supportive home environment (better parental teamwork, less crowding) predicting membership in this group.Conclusions Alongside factors predicting neurodevelopment variance at age 5-years, trajectory analysis identified developmental catch-up among at-risk children, with maternal and home factors predicting recovery.