Phytoplankton contribute to nearly half of the global net primary productivity (NPP) and are critical for marine ecosystems and global food security. Significant changes in ocean temperature, sea surface salinity (SSS), Mixed Layer Depth (MLD), ocean heat content (OHC), pH and dissolved oxygen (O₂) at upper 200 m and that averaged between 200 and 600 m to represent the Oxygen Minimum Zones (OMZ) are identified as the key stressors of marine ecosystem. Here, we examine the changes in stressors and their impact on NPP in the north Indian Ocean (NIO) and its major upwelling zones. There is an increase in SST and freshening in the high saline regions as analysed from the Coupled Model Intercomparison Project 6 (CMIP6) Shared Socioeconomic Pathways (SSP) future (2015–2100) projections, which would reduce NPP in NIO in future. We identify MLD, O₂ in 0–200 m and OMZ as the main factors controlling NPP in the present (2003–2014) period, but SSS and O₂ in 0–200 m and OMZ in the future SSP scenarios. Contribution analysis indicates the dominant role of O₂ in modulating NPP in the future scenarios in the upwelling regions (e.g. Northern AS, Somali Coast and South of Sri Lanka). Future projections also suggest a decreasing trend in pH across different SSP scenarios and its highest negative trend (-0.003 ± 11.12 × 10^-5) is observed in SSP 3–7.0. These changes are more evident in Arabian Sea and its adjoining upwelling regions, but a dominant role of SSS in changing NPP is present in BoB and its upwelling regions. The interaction of stressors is manifested well in West Coast and East coast of India, where circulation and currents have dominant roles in the exchanges of temperature and salt fluxes between the regions. Changes in NPP in these dynamically active regions are controlled by all stressors unlike in other regions. Henceforth, our study provides new insights on the impact of spatio-temporal changes in stressors on the primary productivity of NIO.