A composite based on calcium sulphate hemihydrate enhanced with Zn- or B-doped hydroxyapatite nanoparticles was fabricated and evaluated for bone graft applications. The investigations of their structural and morphological properties were performed by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and energy dispersive X-ray (EDX) spectroscopy techniques. To study the bioactive properties of the obtained composites, soaking tests in simulated body fluid (SBF) were performed. The results showed that the addition of 2% Zn results in an increase of 2.27% in crystallinity, while the addition of boron causes an increase of 5.61% compared to the undoped HAp sample. The crystallite size was found to be 10.69 ± 1.59 nm for HAp@B, and in the case of HAp@Zn, the size reaches 16.63 ± 1.83 nm, compared to HAp, whose crystallite size value was 19.44 ± 3.13 nm. The mechanical resistance of the samples doped with zinc was the highest and decreased by about 6% after immersion in SBF. Mixing HAp nanoparticles with gypsum improved cell viability compared to HAp for all concentrations (except for 200 µg/mL). Cell density decreased with increasing nanoparticle concentration, compared to gypsum, where the cell density was not significantly affected. The degree of cellular differentiation of osteoblast-type cells was more accentuated in the case of samples treated with G+HAp@B nanoparticles compared to HAp@B. Cell viability in these samples decreased inversely proportionally to the concentration of administered nanoparticles. From the point of view of cell density, this confirmed the quantitative data.