Abstract Successfully addressing mental health challenges demands comprehensive, community-driven solutions. Social prescribing (SP) emerges as an innovative approach, fostering integrated care by connecting healthcare patients to community resources. Research in this topic proved effects of SP in mental health and well-being promotion, but factors influencing patients’ uptake remain underexplored. This study examined the factors associated with the uptake in patients with mental health needs in SP project in Portugal. This mixed methods study examined registries data of 403 patients referred to SP for mental health needs. A logistic regression was used to analyse sociodemographic characteristics and referral details associated with SP uptake. Semi-structured interviews were conducted with stakeholders to explore challenges and facilitators of users uptake. Most users were female (71.7%) and elder (average age 64.4 years, SD ± 20.0). Mental health needs included social isolation, loneliness, anxiety, and depression. 43.7% of referred patients had diagnosed mental illnesses and 55.8% attended at least one SP appointment. SP uptake was more likely among patients referred for social and financial support (OR 2.02; 95%CI 1.32-3.07; p = 0.001) and referred during the Covid-19 period (OR 1.64; 95%CI 1.08-2.49; p = 0.020). increased the probability of SP uptake. In contrast, SP uptake was less likely among those having diabetes (OR 0.49; 95%CI 0.28-0.88; p = 0.016). Health professionals’ proactive engagement with patients facilitated uptake in SP, yet challenges arose from users’ complex needs, low awareness, motivation, and acceptance of non-traditional responses such as community-based activities, along with mistrust of their effectiveness. SP has the potential to foster mental health and well-being through person-centred holistic care, yet challenges in uptake related to health and psychosocial factors must be addressed to optimize the SP positive impacts. Key messages • Factors influencing the uptake of patients with mental health needs in SP initiative in Portugal involved need of social and financial support, pandemic period and health professionals’ attitudes. • Despite SP potential, for effective implementation it is key to address challenges, like complexity of patients’ needs, awareness gaps and patient mistrust, to maximize its positive outcomes.