<p><i>Escherichia coli</i> (<i>E. coli</i>), especially enterotoxigenic (ETEC) and extraintestinal pathogenic (ExPEC) strains, remains a leading cause of diarrheal and systemic infections worldwide. Despite decades of extensive research, no licensed <i>E. coli</i> vaccine for human use is currently available. A comprehensive and updated synthesis of evidence from human clinical studies is timely. We performed a systematic review of clinical trials published between January 1, 2000, and October 24, 2024, identified through PubMed, Web of Science, Scopus, and ClinicalTrials.gov. Only original clinical studies of prophylactic vaccines were included; therapeutic. Forty-two studies met the inclusion criteria: 34 on ETEC, 6 on ExPEC, and 2 on other pathotypes. Vaccine platforms included inactivated/killed whole-cell (<i>n</i> = 14), subunit (<i>n</i> = 12), live-attenuated (<i>n</i> = 9), and conjugate vaccines (<i>n</i> = 7). Most vaccine candidates induced measurable immune responses. Among the ten trials that reported efficacy outcomes, two presented high levels of protection, six were associated with reductions in disease severity, and two demonstrated no protective effect. Safety profiles were generally favorable. By identifying patterns of success alongside persistent gaps, this review aims to inform the rational design and strategic prioritization of next-generation <i>E. coli</i> vaccine candidates. Progress will require standardized efficacy trials, multivalent platforms, and optimized mucosal adjuvants to advance candidates toward licensure.</p>