<p>The purpose of the present study was to explore the experiences of two-spirit, lesbian, gay, bisexual, transgender, queer or questioning, intersex, asexual, or otherwise gender or sexually diverse (2SLGBTQIA+) couples pursuing third-party reproduction (TPR). A sample of 31 2SLGBTQIA+ couples (<i>n</i> = 62) from the USA and Canada attempting to conceive via third-party reproduction were recruited online, underwent a semi-structured interview about their experiences, and completed an online survey assessing fertility quality of life, anxious and depressive symptoms, and institutional betrayal in healthcare. Descriptive statistics were used to assess mean levels of quality of life, mental health symptoms, and institutional betrayal. Rates of clinically significant reductions in quality of life and mental health were assessed. Thematic analysis was applied to the interview transcripts. Data were collected between November 2021 and July 2022. Thematic analysis identified numerous challenges in pursuing TPR, many of which were specifically tied to participants’ membership in the 2SLGBTQIA+ community. Two overarching themes were identified: “system-level issues,” such as a lack of information pertaining to their unique situation, and “provider-level issues,” such as the holding of heteronormative assumptions by providers. Quantitative findings revealed that a large proportion of the sample, 34%, scored in the clinical range on anxiety and depression questionnaires. The intended gestating partners reported poorer quality of life relative to their non-gestating partners. 2SLGBTQIA+ couples attempting to conceive via third-party reproduction experience psychological distress and reduced quality of life and face inequities and challenges at the system and provider level. These findings lead to concrete recommendations for clinicians providing fertility services to cultivate competence and improve care standards for this population according to their ethical responsibility and highlight the need for policy change and the development of targeted supports. Key recommendations include 2SLGBTQIA+-specific training for staff, using inclusive language, visuals, and documentation processes, refraining from hetero- and cisnormative assumptions, developing anti-discrimination policy and a process to assess and respond to clients’ mental health needs, and identifying and sharing information and supports.</p>