To estimate the independent and combined effects of in utero exposures on birth outcomes in a rural population.The study used population-level data (2020-2022) from a state-wide surveillance tool (Project WATCH) in West Virginia. Outcomes included low birth weight (LBW), preterm birth, small for gestational age (SGA), and birth weight in grams. Exposure included a composite variable with 8-levels of three exposure (opioids, stimulants, and cannabis) categories. Analyses were adjusted for sociodemographic covariates using multiple logistic and linear regression analyses.Of the 34,412 singleton live births, 1-in-8 newborns (12.2%) had in utero exposure(s) to opioids, stimulants, and/or cannabis, 11.5% were preterm, 7.9% had LBW, 9.6% were SGA, and mean birth weight was 3249g (SD=563.6). Preterm birth was associated with stimulant alone exposure [aOR=1.40 (1.03, 1.89)] and 'stimulant and cannabis' concurrent exposure [aOR =1.69 (1.16, 2.47)]. LBW was associated with opioids alone [aOR=1.34 (1.10, 1.63)], cannabis alone [aOR=1.31 (1.13, -1.52)], 'opioid and cannabis' [aOR=1.61 (1.12, -2.31)], and 'opioids, stimulants, and cannabis' concurrent exposures [aOR=2.27 (1.43, 3.61)]. Five exposure categories were associated with lower birth weights [adjusted mean difference (aMD) range -72g. to -211g)]. SGA was associated with opioids alone [aOR=1.48 (1.24, 1.78)], cannabis alone [aOR=1.49 (1.31, 1.69)], and 'opioids and cannabis' concurrent exposures [aOR=1.91 (1.36, 2.67)].We showed complex associations between in utero substance exposures, preterm birth, birth weight, and sociodemographic factors in a rural population. The results may inform policy efforts to improve maternal and child health in socioeconomically disadvantaged and underserved rural populations.