Cancer screening is a complex process involving multiple steps and levels of influence (e.g., patient, provider, facility, health care system, community, or neighborhood). We describe the design, methods, and research agenda of the Population-based Research to Optimize the Screening Process (PROSPR II) consortium. PROSPR II Research Centers (PRC), and the Coordinating Center aim to identify opportunities to improve screening processes and reduce disparities through investigation of factors affecting cervical, colorectal, and lung cancer screening in U.S. community health care settings. We collected multilevel, longitudinal cervical, colorectal, and lung cancer screening process data from clinical and administrative sources on >9 million racially and ethnically diverse individuals across 10 heterogeneous health care systems with cohorts beginning January 1, 2010. To facilitate comparisons across organ types and highlight data breadth, we calculated frequencies of multilevel characteristics and volumes of screening and diagnostic tests/procedures and abnormalities. Variations in patient, provider, and facility characteristics reflected the PROSPR II health care systems and differing target populations. PRCs identified incident diagnoses of invasive cancers, in situ cancers, and precancers (invasive: 372 cervical, 24,131 colorectal, 11,205 lung; in situ: 911 colorectal, 32 lung; precancers: 13,838 cervical, 554,499 colorectal). PROSPR II’s research agenda aims to advance: (i) conceptualization and measurement of the cancer screening process, its multilevel factors, and quality; (ii) knowledge of cancer disparities; and (iii) evaluation of the COVID-19 pandemic’s initial impacts on cancer screening. We invite researchers to collaborate with PROSPR II investigators. PROSPR II is a valuable data resource for cancer screening researchers.