ABSTRACT The 21-cm line emitted by neutral hydrogen is the most promising probe of the Epoch of Reionization (EoR). Multiple radio interferometric instruments are on the cusp of detecting its power spectrum. It is therefore essential to deliver robust theoretical predictions, enabling sound inference of the coeval Universe properties. The nature of this signal traditionally required the modelling of $\mathcal {O}(10^{7-8} \, {\rm Mpc}^3)$ volumes to suppress the impact of cosmic variance. However, the recently proposed Fixed & Paired (F&P) approach uses carefully crafted simulation pairs to achieve equal results in smaller volumes. In this work, we thoroughly test the applicability of and improvement granted by this technique to different observables of the 21-cm signal from the EoR. We employ radiation-magneto-hydrodynamics simulations to ensure the most realistic physical description of this epoch, greatly improving over previous studies using a seminumerical approach without accurate galaxy formation physics and radiative transfer. We estimate the statistical improvement granted by the F&P technique on predictions of the skewness, power spectrum, bispectrum, and ionized regions size distribution of the 21-cm signal at redshift 7 ≤ z ≤ 10 (corresponding to ${\ge}80{{\ \rm per\ cent}}$ of the gas being neutral). We find that the effective volume of F&P simulations is at least 3.5 times larger than traditional simulations. This directly translates into an equal improvement in the computational cost (in terms of time and memory). Finally, we confirm that a combination of different observables like skewness, power spectrum, and bispectrum across different redshifts can be utilized to maximize the improvement.