Background Despite the initial evidence supporting the utility of intravascular imaging to guide percutaneous coronary intervention (PCI), adoption remains low. Recent new trial data have become available. An updated study‐level meta‐analysis comparing intravascular imaging to angiography to guide PCI was performed. This study aimed to evaluate the clinical outcomes of intravascular imaging–guided PCI compared with angiography‐guided PCI. Methods and Results A random‐effects meta‐analysis was performed on the basis of the intention‐to‐treat principle. The primary outcomes were major adverse cardiac events, cardiac death, and all‐cause death. Mixed‐effects meta‐regression was performed to investigate the impact of complex PCI on the primary outcomes. A total of 16 trials with 7814 patients were included. The weighted mean follow‐up duration was 28.8 months. Intravascular imaging led to a lower risk of major adverse cardiac events (relative risk [RR], 0.67 [95% CI, 0.55–0.82]; P <0.001), cardiac death (RR, 0.49 [95% CI, 0.34–0.71]; P <0.001), stent thrombosis (RR, 0.63 [95% CI, 0.40–0.99]; P =0.046), target‐lesion revascularization (RR, 0.67 [95% CI, 0.49–0.91]; P =0.01), and target‐vessel revascularization (RR, 0.60 [95% CI, 0.45–0.80]; P <0.001). In complex lesion subsets, the point estimate for imaging‐guided PCI compared with angiography‐guided PCI for all‐cause death was a RR of 0.75 (95% CI, 0.55–1.02; P =0.07). Conclusions In patients undergoing PCI, intravascular imaging is associated with reductions in major adverse cardiac events, cardiac death, stent thrombosis, target‐lesion revascularization, and target‐vessel revascularization. The magnitude of benefit is large and consistent across all included studies. There may also be benefits in all‐cause death, particularly in complex lesion subsets. These results support the use of intravascular imaging as standard of care and updates of clinical guidelines.