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Background: Colorectal cancer (CRC) incidence at ages <50 years is increasing worldwide. Screening initiation was lowered to 45 years in the United States. The cost‐effectiveness of initiating CRC screening at 45 years in Israel was assessed with the aim of informing national policy and addressing internationally relevant questions. Methods: A validated CRC screening model was calibrated to Israeli data and examined annual fecal immunochemical testing (FIT) or colonoscopy every 10 years from 45 to 74 years (FIT45‐74 or Colo45‐74) versus from 50 to 74 years (FIT50‐74 or Colo50‐74). The addition of a fourth colonoscopy at 75 years was explored, subanalyses were performed by sex/ethnicity, and resource demands were estimated. Results: FIT50‐74 and Colo50‐74 reduced CRC incidence by 57% and 70% and mortality by 70% and 77%, respectively, versus no screening, with greater absolute impact in Jews/Other versus Arabs but comparable relative impact. FIT45‐74 further reduced CRC incidence and mortality by an absolute 3% and 2%, respectively. With Colo45‐74 versus Colo50‐74, CRC cases and deaths increased slightly as three colonoscopies per lifetime shifted to 5 years earlier but mean quality‐adjusted life‐years gained (QALYGs) per person increased. FIT45‐74 and Colo45‐74 cost 23,800–53,900 new Israeli shekels (NIS)/QALYG and 110,600–162,700 NIS/QALYG, with the lowest and highest values among Jewish/Other men and Arab women, respectively. A fourth lifetime colonoscopy cost 48,700 NIS/QALYG. Lowering FIT initiation to 45 years with modest participation required 19,300 additional colonoscopies in the first 3 years. Conclusions: Beginning CRC screening at 45 years in Israel is projected to yield modest clinical benefits at acceptable costs per QALYG. Despite different estimates by sex/ethnicity, a uniform national policy is favored. These findings can inform Israeli guidelines and serve as a case study internationally. In a modeling study of colorectal cancer (CRC) screening in Israel, where CRC incidence at ages <50 years has not increased, lowering CRC screening initiation to 45 years yielded moderate clinical benefits at acceptable costs. [ABSTRACT FROM AUTHOR]