Intracoronary imaging (ICI) facilitates stent implant by characterizing the lesion calcification, providing accurate vessel dimensions, and optimizing the stent results. We sought to investigate the outcomes of routine ICI versus coronary angiography (CA) to guide percutaneous coronary intervention (PCI) with second- and third-generation drug-eluting stents. A systematic search of PubMed, Medline, and Cochrane databases was conducted from their inception to July 16, 2022 for randomized controlled trials comparing routine ICI with CA. The primary outcome was major adverse cardiovascular events. The secondary outcomes of interest were target lesion revascularization, target vessel revascularization, myocardial infarction, stent thrombosis, and cardiac and all-cause mortality. A random-effects model was used to calculate the pooled incidence and relative risk (RR) with 95% confidence intervals (CIs). A total of 9 randomized controlled trials with 5,879 patients (2,870 ICI-guided and 3,009 CA-guided PCI) met the inclusion criteria. The ICI and CA groups were similar in demographic characteristics and co-morbidity profiles. Compared with CA, patients in the routine ICI-guided PCI group had lower rates of major adverse cardiovascular events (RR 0.61, 95% CI 0.48 to 0.78, p <0.0001), target lesion revascularization (RR 0.60, 95% CI 0.43 to 0.83, p = 0.002), target vessel revascularization (RR 0.72, 95% CI 0.51 to 1.00, p = 0.05), and myocardial infarction (RR 0.48, 95% CI 0.25 to 0.95, p = 0.03). There were no significant differences in stent thrombosis or cardiac/all-cause mortality between the 2 strategies. In conclusion, routine ICI-guided PCI strategy, compared with CA guidance alone, is associated with improved clinical outcomes, largely driven by lower repeat revascularization.