Intracellular pathogens manipulate host cellular pathways to ensure their survival. Mycobacterium tuberculosis (Mtb) disrupts phagosomal trafficking to prevent fusion with lysosomes. Beyond this localized effect, Mtb globally remodels the host lysosomal system, predominantly through its virulence-associated surface lipid, sulfolipid-1 (SL-1). SL-1 enhances lysosomal biogenesis via the mTORC1-TFEB axis; however, the upstream mediators remain unknown. Here, we show that SL-1 induces calcium influx into macrophages and identify the mechanosensitive calcium channel transient receptor potential vanilloid subtype 4 (TRPV4) as a crucial upstream mediator of SL-1-induced lysosomal remodeling. TRPV4 influences multiple aspects of lysosomal function, including biogenesis, acidification, enzymatic activity, phagosome maturation, and lysosomal exocytosis. These effects are recapitulated during Mtb infection, underscoring the relevance of SL-1- and TRPV4-dependent lysosomal remodeling in an infection context. TRPV4 expression is upregulated during Mtb infection and partially localizes to both lysosomes and the Mtb-containing vacuole. Remarkably, TRPV4 activation, independent of SL-1, is sufficient to enhance lysosomal biogenesis, identifying TRPV4 as a key regulator of lysosomal homeostasis. Together, these findings uncover a novel mechanism of lysosomal remodeling driven by a pathogen lipid virulence factor and reveal a previously unrecognized role for TRPV4 in modulating lysosomal homeostasis in macrophages.