Photodynamic　therapy　(PDT)　is　a　noninvasive　and　effective　approach　in　clinical　cancer　treatments.　Boron-dipyrromethene　(BODIPY)-based　derivatives　have　emerged　as　novel　and　promising　photosensitizers　(PSs)　in　PDT,　attributed　to　their　strong　near-infrared　singlet　oxygen　luminescence　emissions　and　high　photostabilities.　However,　the　binding　mechanism　of　BODIPY　derivatives　to　proteins,　key　for　their　therapeutic　and　biomedical　applications　is　still　poorly　understood.　Here,　we　investigated　the　molecular　interactions　of　two　2,　6-diiodo-BODIPY　derivatives　with　human　serum　albumin　(HSA)　using　combined　experimental　and　computational　techniques.　Our　spectroscopic　results　showed　that　both　BODIPY　derivatives　formed　stable　complexes　with　HSA.　Strikingly,　the　BODIPY/HSA　complexes　exhibited　notably　enhanced　water　solubility　and　singlet　oxygen　generation　efficiency　with　respect　to　the　BODIPY　alone.　Furthermore,　molecular　docking,　molecular　dynamics　simulations,　and　binding　free　energy　calculations　provided　the　structural　and　energetic　insights　into　the　binding　mechanism　of　BODIPY-based　derivatives　to　HSA.　Our　work　demonstrated　that　conjugation　of　BODIPYs　with　HSA　may　be　a　promising　strategy　to　enhance　the　performance　of　BODIPY-based　PSs,　and　the　combination　of　computational　and　experimental　techniques　is　expected　to　play　key　roles　in　the　design　and　development　of　novel　PSs　with　improved　bioavailability　and　biocompatibility　for　cancer　therapeutic　applications.　©　2018