Capacitive crosstalk noise can affect the delay of a switching signal or induce a glitch on a static signal causing timing violations or chip failure. Crosstalk noise depends on coupling parasitics, driver strength, signal timing characteristics, and signal transition patterns. Layout level crosstalk analysis techniques are generally pessimistic and computationally expensive for large designs due to lack of design flexibility at lower-levels of design hierarchy. The architectural decisions such as type of interconnect architecture, number of storage and execution units, network of communicating units, data bus width, etc., have a major impact on the quality of design attributes such as area, speed, power, and noise. To address all these concerns, we propose a high-level synthesis framework to optimize for worst-case crosstalk patterns on coupled nets, a floorplan driven high-level synthesis framework to minimize coupling capacitance, and an on-chip technique to dynamically detect and eliminate worst-case crosstalk pattern on bus-based macro-cell designs. Due to Miller coupling effect, the switching activity pattern on adjacent nets may increase the effective capacitance seen by a victim net and thereby it may cause a worst-case signal delay on the victim net. However, signal activity pattern on coupled nets are dependent on data correlations which in turn depend on resource sharing. The resource sharing in turn depends on scheduling, allocation, and binding during high-level synthesis flow. Therefore, we propose a Simulated Annealing (SA) based design space exploration of HLS design subspace, bus line re-ordering, and encoding subspaces to optimize for worst-case crosstalk pattern in bus-based macro-cell designs. We demonstrate that the proposed framework will aid layout level techniques in eliminating false positive violations. We also propose an SA based algorithm to explore floorplan and HLS subspaces to optimize coupling capacitances in bus-based macro-cell designs. We have integrated an RTL floorplanner in HLS flow to estimate coupling capacitances between bus lines. Crosstalk analysis using Cadence Celtic shows that the designs generated by the proposed framework results in less number of crosstalk violations compared to designs generated through traditional ASIC design flow. We also propose an on-chip crosstalk detection and elimination technique that dynamically detects and eliminates worst-case crosstalk pattern with minimum area penalty compared to other layout level techniques reported in the literature.