Strain engineering is a widely used technique for enhancing the mobility of charge carriers in semiconductors, but its effect has not yet been fully investigated theoretically. In this work, we perform first-principles calculations to explore the variations of the mobility for electrons and holes in silicon upon deformation by uniaxial strain up to 2% in the [100] crystal direction. We compare these theoretical results to the low-strain experimental piezoresistive effect for temperatures from 200 K to 400 K and find good agreement for the electron and hole mobilities. We confirm the small enhancement of the hole mobility observed experimentally at low strain as the latter increases. On top of that, we predict a strong enhancement of the mobility at higher strain. In particular, the hole mobility at 2%-strain is more than twice as large as that of unstrained silicon. Resorting to first-principles calculations is found to be particularly crucial for the holes for which the proximity of the valence bands and the important modification of their shapes under strain conditions limit the accuracy that can be achieved when adopting an analytic approach. Our findings highlight a new perspective to boost mobility, especially for the holes with a stress applied in the [100] direction. Additionally, we illustrate the advantages of using first-principles tools to study the piezoresistive effect in semiconductors.