A significant-loophole-free test of Bell's theorem with entangled photons was conducted, closing the most significant loopholes in previous experiments. The experiment used a well-optimized source of entangled photons, rapid setting generation, and highly efficient superconducting detectors to observe a violation of a Bell inequality with high statistical significance. The probability of the results occurring under local realism was less than 3.74 × 10⁻³¹, corresponding to an 11.5 standard deviation effect. The experiment closed the locality, freedom-of-choice, and fair-sampling loopholes simultaneously. The setup involved entangled photons generated via spontaneous parametric down-conversion, distributed to two distant measurement stations, and measured using polarization analysis. The experiment ensured space-like separation between the measurement settings and the photon emission, and between the measurement settings and the distant measurement. The results strongly support the idea that local realism is untenable. The experiment also closed the coincidence-time and memory loopholes by using locally-defined time slots and computing the statistical significance of the violation without assuming independent and identically distributed experimental trials. The experiment provides the strongest support to date for the viewpoint that local realism is untenable.A significant-loophole-free test of Bell's theorem with entangled photons was conducted, closing the most significant loopholes in previous experiments. The experiment used a well-optimized source of entangled photons, rapid setting generation, and highly efficient superconducting detectors to observe a violation of a Bell inequality with high statistical significance. The probability of the results occurring under local realism was less than 3.74 × 10⁻³¹, corresponding to an 11.5 standard deviation effect. The experiment closed the locality, freedom-of-choice, and fair-sampling loopholes simultaneously. The setup involved entangled photons generated via spontaneous parametric down-conversion, distributed to two distant measurement stations, and measured using polarization analysis. The experiment ensured space-like separation between the measurement settings and the photon emission, and between the measurement settings and the distant measurement. The results strongly support the idea that local realism is untenable. The experiment also closed the coincidence-time and memory loopholes by using locally-defined time slots and computing the statistical significance of the violation without assuming independent and identically distributed experimental trials. The experiment provides the strongest support to date for the viewpoint that local realism is untenable.