Only 40–50% of first-year collegiate science, technology, engineering or math (STEM) students complete a Bachelor of Science degree. Persistence and graduation rates of students from racially minoritized groups that historically have been underrepresented in STEM (URG) is significantly lower. Culturally responsive programming that incorporates the values, perspectives, cultures, and the empathy and equity matters of non-majority populations can empower students from diverse backgrounds to achieve their educational goals. This paper describes the outcomes of first-year place-based learning community students who participated in a water quality laboratory that integrates the science, culture, values, and social justice concerns of the Indigenous people of the Klamath River Basin. The curriculum was designed by university faculty and Indigenous scientists from The Karuk Tribe of California. A combination of survey data and thematic analysis was used to evaluate the impact of our program on intellectual growth, gains in psychosocial factors associated with first year student success, and academic achievement. All student participants demonstrated intellectual growth and gains in psychosocial factors associated with STEM retention, but the effects were most pronounced for students who identified parallels between issues faced by Native American communities and their home community. The most significant gains in STEM retention and academic achievement occurred for URG students who learned about Native American culture through the water quality laboratory. The majority of all students expressed the importance of understanding the cultural, environmental, and/or social justice issues of Native American people to their future careers. We believe ours is one of the first studies that specifically examines the power of collaborating with contemporary Indigenous communities to create opportunities for first-year collegiate STEM students to participate in interdisciplinary, place-based curricular and co-curricular activities.