This study presents new maps of the topographic and geophysical setting and seismicity in the region of the Gulf of Panama. The spatial analysis is based on the comparative analysis of the datasets on geoid, free-air gravity anomaly, topography and earthquakes. The cartographic framework is developed using the Generic Mapping Tools (GMT) scripting toolset. Seismic activity in the Central America is high due to the complex geologic setting, tectonic activity and lithosphere plate subduction. The data include the Earth Gravitational Model (EGM2008), the General Bathymetric Chart of the Oceans (GEBCO) and gravity grids. The seismicity data were collected from the Incorporated Research Institutions for Seismology (IRIS) catalogue on 1970–2021. The variations in data were compared to analyse correlations between the geophysical, seismic and topographic parameters. Free-air gravity, geoid and topographic data derived from the high-resolution datasets were used to investigate their effects on the main seismic sources in the region. The comparison of the maps showed that the distribution of the shallow earthquakes in the Pacific segment of Panama coincides with negative free-air anomalies and lower geoid values. The results revealed high values of geoid in the high mountainous regions of Panama (Cordilliera de Talamanca, southern coast of Peninsula de Azuero and eastern Panama, 77.5–78.5°W), which correspond to the topographic roughness in the highlands. Negative values of geoid are found over the Caribbean Sea basin (−4 to 0 m). The analyses of seismicity showed 1740 earthquake events varying by magnitudes from 2.9 to 7.8 at the depths up to 225 m (near the west coast of Colombia). A high concentration of the earthquakes is in the western region of the Panama’s shelf waters (~82–83.5°W), and on the border with Colombia (~77–78.5°W). High gravity anomalies (over 220 mGal) are found in the mountainous regions which match the geodynamic processes associated with the Earth structure and geodetic and geophysical effects. The regions of the high seismicity were defined in the Gulf of Chiriqui and eastern part of the Gulf of Panama.