There are a growing number of informal science education (ISE) programs in Native communities that engage youth in science education and that are grounded in Native ways of knowing. There is also a growing body of research focusing on the relationship between culture, traditional knowledge, and science education. However, there is little research documenting how these programs are being developed and the ways in which culture and Western science are incorporated into the activities. This study outlines effective practices for using Native ways of knowing to strengthen ISE programs. These effective practices may also be used to promote change in formal education. The authors combine an overview of current research in informal science education with personal interviews with educators engaged in ISE programs offered to youth both on and off tribal reservations as well as experts in Indigenous education. Participating individuals and programs included Native communities across the United States, including Alaska and Hawai'i. Keeping in mind that each community is unique, ISE programs that are grounded in Native ways of knowing will benefit by utilizing the effective practices outlined here as a guide for starting or strengthening existing ISE programs relevant to the needs of their communities.