Background The proliferation of International Investment Agreements (IIAs), as the result of globalization, has been identified as one of the factors contributing to policy inertia or chill on meaningful public health policy action. Health safeguards, i.e., specific clauses to protect the State’s right to regulate, have been increasingly included in IIAs to protect health policy. However, an in-depth understanding of the processes involved in the diffusion of health safeguards in IIAs globally and the factors acting as barriers and facilitators for their uptake is still lacking. In this context, the present study intends to fill this research gap by analysing the uptake of health safeguards in the context of Uruguay, a developing Latin American country. The objectives were to: (i) examine the evolution of the inclusion of health safeguards in the Bilateral Investment Treaties (BITs) signed by Uruguay until 2024, (ii) analyse how Uruguay has approached BITs after the Philip Morris ISDS case, (iii) explore Uruguayan stakeholders’ perspectives on the inclusion of health safeguards in BITs, (iv) identify barriers and facilitators for the uptake of health safeguards in the BITs. Results Documentary analysis of the BITs signed by Uruguay showed an ascending trend in the inclusion of health safeguards, reaching 100% since 2010. Interviews with key stakeholders suggested that health safeguards diffused from abroad through transnational transfer networks. While Uruguay has not faced challenges in including health safeguards in recent BITs, the renegotiation of old generation BIT agreements with developed countries has proven to be difficult. A wide range of factors that act as facilitators and barriers for the inclusion for health safeguards in the BITs were identified, which were related to both the national and intergovernmental levels. Conclusions Results contribute to the understanding of the factors that influence the evolution of the interface between investment agreements and public health policy by analysing the adoption of health safeguards in BITs. Strong recommendations from international organizations to renegotiate old generation BITs may contribute to overcoming the existing power dynamics and support developing countries in the protection of their regulatory space.