General practitioners (GPs) report high levels of distress. This study examined whether a brief blended web-based mindfulness intervention could be effective at enhancing well-being for GPs and assessed the possible mediating role of awareness. An open uncontrolled trial, with pre-post measurements, was conducted. The programme comprised one face-to-face meeting (4 h) and eight online practice sessions with no support (two weekly sessions over 4 weeks). The primary outcome was positive affect (PANAS-positive). The secondary outcomes were as follows: negative affect (PANAS-negative), awareness (MAAS), resilience (CDRISC), and the burnout subtypes (BCSQ-12). Mixed-effects analysis for repeated measures and mediation analysis by regression models were performed. Two hundred ninety Spanish GPs took part in the study, attending the face-to-face meeting. Nearly one out 10 participants (n = 28) completed ‘one weekly practice’, and 10.4% (n = 30) accomplished ‘two or more weekly practices’. There were benefits for those with ‘two or more weekly practices’ in PANAS-positive (B = 2.97; p = 0.007), and MAAS (B = 4.65; p = 0.023). We found no benefits for those with ‘one weekly practice’ in any of the outcomes. There were mediating effects of MAAS in PANAS-positive (explaining a 60.8% of total effects). A brief blended mindfulness intervention, with minimum face-to-face contact and web-based practice sessions, seems to confer improvements in the well-being of Spanish GPs. The benefits may be mediated by awareness. The implementation of this kind of programme might enhance the well-being among GPs, but there is a need to improve adherence to practice. Further research using randomized controlled designs will be needed to support the evidence found in our study.