Background Short chain fatty acids (SCFAs) are microbially derived end products of dietary fiber fermentation. The SCFA butyrate reduces blood pressure (BP) in mouse models. The association of SCFAs, including butyrate, with BP in humans is unclear, due in part to predominantly cross‐sectional analyses and different biospecimens (blood versus fecal) for SCFA measurement. Longitudinal studies including both circulating and fecal SCFAs are lacking. Methods and Results We leveraged existing data from the SPIRIT (Survivorship Promotion In Reducing IGF‐1 Trial), which randomized 121 adult cancer survivors with overweight/obesity to a behavioral weight‐loss intervention, metformin, or self‐directed weight‐loss. Of participants with baseline serum and fecal SCFAs measured (n=111), a subset had serum (n=93) and fecal (n=89) SCFA measurements 12 months later. We used Poisson regression with robust error variance to estimate baseline associations of SCFAs with hypertension, and we assessed the percent change in SCFAs from baseline with corresponding 12‐month changes in BP using multiple linear regression. Baseline fecal butyrate was inversely associated with prevalent hypertension (standardized PR [95%CI]: 0.71 [0.54, 0.92]). A 10% increase in fecal butyrate from baseline was associated with decreased systolic BP (β [95%CI]: −0.56 [−1.01, −0.10] mm Hg), and a 10% increase in serum butyrate was associated with decreased systolic (β [95%CI]: −1.39 [−2.15, −0.63] mm Hg) and diastolic (β [95%CI]: −0.55 [−1.03, −0.08] mm Hg) BPs. Butyrate associations with systolic BP were linear and not modified by sex, race, or intervention arm. Conclusions Increased serum or fecal butyrate is associated with lowered BP. Butyrate may be a target for SCFA‐centered BP‐lowering interventions. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02431676.