The study examines the levels of total mercury (Hg) and selenium (Se) in the muscle tissue of 12 commercially important fish species (n = 717) from 48 locations in the eastern Adriatic Sea, as a function of fish species, size and habitat. Risks and benefits of fish consumption regarding Hg and Se in children (7 years) and women of reproductive age (30 years) were also evaluated. All samples but one were compliant with the European regulatory limit for Hg in fish muscle. Concentrations (μg g−1 ww) of Hg (range: 0.014–1.37) and Se (range: 0.184–1.12) and Se:Hg molar ratios in fish were associated with habitat type. Demersal species had the highest Hg and the lowest Se concentrations, while pelagic species had the lowest Hg concentrations, highest Se concentrations and Se:Hg molar ratios. All species had Se:Hg molar ratios above 1 (range: 1.4–66.9) and a selenium health benefit value (HBVSe) above zero (range: 3.3–9.3), indicating Se excess after Hg sequestration. The intake of two meals per week of small pelagic-neritic and bento-pelagic fish is estimated to be a valuable source of essential Se, and does not pose a risk from toxic Hg exposure in children and women during the vulnerable reproductive period. Due to the low Hg and favorable Se:Hg molar ratio and HBVSe index, small pelagic species offer a good risk to benefit ratio of fish consumption and could be considered an optimal choice in these sensitive subpopulations.