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Abstract Quantum materials are often characterized by a marked sensitivity to minute changes in their physical environment, a property that can lead to new functionalities and thereby, to novel applications. One such key property is the magneto-elastoresistance (MER), the change in magnetoresistance (MR) of a metal induced by uniaxial strain. Understanding and modeling this response can prove challenging, particularly in systems with complex Fermi surfaces. Here, we present a thorough analysis of the MER in the nearly compensated Dirac nodal-line semi-metal ZrSiSe. Small amounts of strain (0.27%) lead to large changes (7%) in the MR. Subsequent analysis reveals that the MER response is driven primarily by a change in transport mobility that varies linearly with the applied strain. This study showcases how the effect of strain tuning on the electrical properties can be both qualitatively and quantitatively understood. A complementary Shubnikov-de Haas oscillation study sheds light on the root of this change in quantum mobility. Moreover, we unambiguously show that the Fermi surface consists of distinct electron and hole pockets revealed in quantum oscillation measurements originating from magnetic breakdown.