This Letter reports the first scientific results from the observation of antineutrinos emitted by fission products of 235U at the High Flux Isotope Reactor. PROSPECT, the Precision Reactor Oscillation and Spectrum Experiment, consists of a segmented 4 ton 6Li-doped liquid scintillator detector covering a baseline range of 7–9 m from the reactor and operating under less than 1 m water equivalent overburden. Data collected during 33 live days of reactor operation at a nominal power of 85 MW yield a detection of 25 461 ± 283 (stat) inverse beta decays. Observation of reactor antineutrinos can be achieved in PROSPECT at 5σ statistical significance within 2 h of on-surface reactor-on data taking. A reactor model independent analysis of the inverse beta decay prompt energy spectrum as a function of baseline constrains significant portions of the previously allowed sterile neutrino oscillation parameter space at 95% confidence level and disfavors the best fit of the reactor antineutrino anomaly at 2.2σ confidence level.